Boronic acid derivatives

ABSTRACT

Compounds of formula (I) are inhibitors of LMP7 and can be employed, inter alia, for the treatment of an autoimmune disorder or hematological malignancies.

CROSS-REFERENCE TO RELATED APPLICATION

This application is the U.S. national stage application of InternationalPatent Application No. PCT/EP2015/001930, filed Oct. 1, 2015.

FIELD OF THE INVENTION

The present invention relates to α-Amino boronic acid derivatives. Thesecompounds are useful for inhibiting the activity of immunoproteasome(LMP7) and for the treatment and/or prevention of medical conditionsaffected by immunoproteasome activity such as inflammatory andautoimmune diseases, neurodegenerative diseases, hematologicalmalignancies and proliferative diseases. In particular, the compounds ofthe present invention are selective immunoproteasome inhibitors.

BACKGROUND TO THE INVENTION

The proteasome (also known as macropain, the multicatalytic protease,and 20S protease) is a high molecular weight, multisubunit proteasewhich has been identified in every examined species from anarchaebacterium to human. The enzyme has a native molecular weight ofapproximately 650,000 and, as revealed by electron microscopy, adistinctive cylinder-shaped morphology (Rivett, (1989) Arch. Biochem.Biophys. 268:1-8; and Orlowski, (1990) Biochemistry 29:10289-10297). Theproteasome subunits range in molecular weight from 20,000 to 35,000, andare homologous to one another but not to any other known protease.

The 20S proteasome is a 700 kDa cylindrical-shaped multicatalyticprotease complex comprised of 28 subunits, classified as α- and β-type,that are arranged in 4 stacked heptameric rings. In yeast and othereukaryotes, 7 different a subunits form the outer rings and 7 differentβ subunits comprise the inner rings. The a subunits serve as bindingsites for the 19S (PA700) and 1 IS (PA28) regulatory complexes, as wellas a physical barrier for the inner proteolytic chamber formed by thetwo β subunit rings. Thus, in vivo, the proteasome is believed to existas a 26S particle (“the 26S proteasome”). In vivo experiments have shownthat inhibition of the 20S form of the proteasome can be readilycorrelated to inhibition of 26S proteasome.

Cleavage of amino-terminal prosequences of β subunits during particleformation exposes amino-terminal threonine residues, which serve as thecatalytic nucleophiles. The subunits responsible for catalytic activityin proteasome thus possess an amino terminal nucleophilic residue, andthese subunits belong to the family of N-terminal nucleophile (Ntn)hydrolases (where the nucleophilic N-terminal residue is, for example,Cys, Ser, Thr, and other nucleophilic moieties). This family includes,for example, penicillin G acylase (PGA), penicillin V acylase (PVA),glutamine PRPP amidotransferase (GAT), and bacterialglycosylasparaginase. In addition to the ubiquitously expressed βsubunits, higher vertebrates also possess three interferon-γ-inducible βsubunits (LMP7, LMP2 and MECLI), which replace their normalcounterparts, β5, β1 and β2, respectively. When all threeIFN-γ-inducible subunits are present, the proteasome is referred to asan “immunoproteasome”. Thus, eukaryotic cells can possess two forms ofproteasomes in varying ratios.

Through the use of different peptide substrates, three major proteolyticactivities have been defined for the eukaryote 20S proteasomes:chymotrypsin-like activity (CT-L), which cleaves after large hydrophobicresidues; trypsin-like activity (T-L), which cleaves after basicresidues; and peptidylglutamyl peptide hydrolyzing activity (PGPH),which cleaves after acidic residues. Two additional less characterizedactivities have also been ascribed to the proteasome: BrAAP activity,which cleaves after branched-chain amino acids; and SNAAP activity,which cleaves after small neutral amino acids. Although both forms ofthe proteasome possess all five enzymatic activities, differences in theextent of the activities between the forms have been described based onspecific substrates. For both forms of the proteasome, the majorproteasome proteolytic activities appear to be contributed by differentcatalytic sites within the 20S core.

In eukaryotes, protein degradation is predominately mediated through theubiquitin pathway in which proteins targeted for destruction are ligatedto the 76 amino acid polypeptide ubiquitin. Once targeted, ubiquitinatedproteins then serve as substrates for the 26S proteasome, which cleavesproteins into short peptides through the action of its three majorproteolytic activities. While having a general function in intracellularprotein turnover, proteasome-mediated degradation also plays a key rolein many processes such as major histocompatibility complex (MHC) class Ipresentation, apoptosis and cell viability, antigen processing, NF-κBactivation, and transduction of pro-inflammatory signals.

Proteasome activity is high in muscle wasting diseases that involveprotein breakdown such as muscular dystrophy, cancer and AIDS. Evidencealso suggests a possible role for the proteasome in the processing ofantigens for the class I MHC molecules (Goldberg, et al. (1992) Nature357:375-379).

Proteasomes are involved in neurodegenerative diseases and disorderssuch as Amyotrophic Lateral Sclerosis (ALS), (J Biol Chem 2003, Allen Set al., Exp Neurol 2005, Puttaparthi k et al.), Sjogren's syndrome(Arthritis & Rheumatism, 2006, Egerer T et al.), systemic lupuserythematoses and lupus nephritis (SLE/LN), (Arthritis & rheuma 2011,Ichikawa et al., J Immunol, 2010, Lang V R et al., Nat Med, 2008,Neubert K et al), glomerulonephritis (J Am Soc nephrol 2011, Bontscho etal.), Rheumatoid Arthritis (Clin Exp Rheumatol, 2009, Van der Heiden J Wet al.), Inflammatory bowel disease (IBD), ulcerative colitis, Crohn'sdiseases, (Gut 2010, Schmidt N et al., J Immunol 2010, Basler M et al.,Clin Exp Immunol, 2009, Inoue S et al.), multiple sclerosis (Eur JImmunol 2008, Fissolo N et al., J Mol Med 2003, Elliott P J et al., JNeuroimmunol 2001, Hosseini et al., J Autoimmun 2000, Vanderlugt C L etal.), Amyotrophic lateral sclerosis (ALS), (Exp Neurol 2005, Puttaparthik et al., J Biol Chem 2003, Allen S et al.), osteoarthritis (Pain 2011,Ahmed s et al., Biomed Mater Eng 2008, Etienne S et al.),Atherosclerosis (J Cardiovasc Pharmacol 2010, Feng B et al., Psoriasis(Genes & Immunity, 2007, Kramer U et al.), Myasthenia Gravis (J Immunol,2011, Gomez A M et al.), Dermal fibrosis (Thorax 2011, Mutlu G M et al.,Inflammation 2011, Koca S S et al., Faseb J 2006, Fineschi S et al.),renal fibrosis (Nephrology 2011 Sakairi T et al.), cardiac fibrosis(Biochem Pharmacol 2011, Ma y et al.,) Liver fibrosis (Am J Physiolgastrointest Liver Physiol 2006, Anan A et al.), Lung fibrosis (Faseb J2006, Fineschi S et al et al.), Immunogloulin A nephropathy (IGanephropathy), (Kidney Int, 2009, Coppo R et al.), Vasculitis (J Am Socnephrol 2011, Bontscho et al.), Transplant rejection (Nephrol Dialtransplant 2011, Waiser J et al.), Hematological malignancies (Br JHaematol 2011, Singh A V et al., Curr Cancer Drug Target 2011, Chen D etal.) and asthma.

Yet, it should be noted that commercially available proteasomeinhibitors inhibit both the constitutive and immuno-forms of theproteasome. Even bortezomib, the FDA-approved proteasome inhibitor forthe treatment of relapsed multiple myeloma patients, does notdistinguish between the two forms (Altun et al., Cancer Res 65:7896,2005). Furthermore, the use of Bortezomib is associated with atreatment-emergent, painful peripheral neuropathy (PN), thisbortezomib-induced neurodegeneration in vitro occurs via aproteasome-independent mechanism and that bortezomib inhibits severalnonproteasomal targets in vitro and in vivo (Clin. Cancer Res, 17(9),May 1, 2011).

In addition to conventional proteasome inhibitors, a novel approach maybe to specifically target the hematological-specific immunoproteasome,thereby increasing overall effectiveness and reducing negativeoff-target effects. It has been shown that immunoproteasome-specificinhibitor, could display enhanced efficiency on cells from a hematologicorigin (Curr Cancer Drug Targets, 11(3), March, 2011).

Thus there is a need to provide new proteasome inhibitors that areselective of one specific form of the proteasome. In particular there isa need to provide selective immunoproteasome inhibitors, which could beused as therapeutic agents for the treatment of e.g. SLE or other immuneor autoimmune disorders in the context of rheumatoid arthritis.Selective immunoproteasome inhibitors are helpful in order to minimizeunwanted side effects mediated by inhibition of the constitutiveproteasome or other nonproteasomal targets.

WO 2013/092979 A1 describes boronic acid derivatives, which showselectivity towards the inhibition of the LMP7 activity. However, theextent of selectivity, which is achievable with the described types ofcompounds, is limited, particularly with respect to the split to theinhibitory activity of the constitutive proteasome.

Unspecific inhibitors of the proteasome and the immunoproteasome likeBortezomib and Carfilzomib have demonstrated their clinical value in theindication of multiple myeloma. Although this unspecific profile,hitting major components in the immunoproteasome as well as theconstitutive proteasome, is regarded as beneficial in terms of targetinhibition and clinical effectiveness, this unspecific profile limitsthe clinical applicability of these agents by inducing pronounced sideeffects like thrombocytopenia, neutropenia as well as peripheralneuropathy. To a certain extent, this side effect profile could beattributed to the broad inhibition of the catalytic activity, especiallythe combined inhibition of the 915 subunits of the constitutive and theimmunoproteasome. The approach to come up with more selective inhibitorsof the immunoproteasome (and especially the ß5i subunit of theimmunoproteasome), in order to reduce major side effects has beendescribed e.g. in 2011 by Singh et al. (Br. J. Hematology 152(2):155-163) for PR-924, a 100 fold selective inhibitor of the LMP7 subunitof the immunoproteasome. The authors demonstrated the presence of highexpression levels of the immunoproteasome in multiple myeloma. Theauthors also described the effect of a selective inhibitor of the LMP7subunit on the induction of cell death in MM cell lines as well asCD138+MM primary patient cells without decreasing the viability ofcontrol PBMC's of healthy volunteers which can be regarded as aconceptual proof. Besides the concept of a reduced side effect profilefor selective 135i inhibitors other groups demonstrated the efficacy ofselective 135i inhibition on the viability of Bortezomib resistant celllines underlining the value and potential perspective for theapplication of selective LMP7 inhibitors for hematological malignancies(D. Niewerth et al./Biochemical Pharmacology 89 (2014) 43-51).

Surprisingly, it was found that amino boronic acid derivatives accordingto this invention also inhibit LMP7. These compounds show very goodproperties in terms of their use in the treatment and/or prevention ofmedical conditions affected by immunoproteasome activity. In particularthe compounds of the present invention are able to inhibit the activityof the immunoproteasome (LMP7) providing a significant split to theinhibitory activity of the constitutive proteasome. Besides this, thestructural assembly of the compounds allows a simple and straightforwardfine-tuning of the compound properties. Further important advantages aretheir good results regarding plasma-protein binding, CYP inhibition, PKprofile and oral bioavailability.

SUMMARY OF THE INVENTION

Compounds of the present invention are inhibitors of theimmunoproteasome subunit LMP7. They show significant selectivity on LMP7over Beta5 (cP) and good properties in terms of solubility,plasma-protein binding, CYP inhibition, PK profile and oralbioavailability.

The present invention provides compounds of formula (I):

wherein

-   LX denotes (CH₂)_(n), wherein 1 to 5H atoms may be replaced by Hal,    R^(3a), OR^(4a), C3-C6-cycloalkyl, Ar2 and/or Het2, and/or wherein 1    or 2 non-adjacent CH₂ groups may be replaced by C3-C6-cycloalkyl, O,    SO and/or SO₂;-   LY denotes (CH₂)_(m), wherein 1 to 5H atoms may be replaced by Hal,    R^(3b) and/or OR^(4b), and/or wherein 1 or 2 non-adjacent CH₂ groups    may be replaced by O, SO and/or SO₂;-   X denotes a 5-, 6-, or 7-membered heterocycle of formula xa) or xb),    each, independently from one another, unsubstituted or mono-, di- or    trisubstituted with A1, Ar1, COA1, COAr1, SO₂A1, SO₂Ar1, and/or    Het1, wherein the ring members other that N and Z are CH₂ groups,    and wherein 1 or 2 of these CH₂ groups may be replaced by C═O, O, S,    NH, NAlk, SO and/or SO₂

-   Y denotes OR^(3c) or Cyc;-   Z denotes C═O or SO₂;-   R¹, R² denote each, independently from one another, H or    C1-C6-alkyl, or R¹ and R² form together a residue of formula (CE)

-   R^(3a), R^(3b), R^(3c) denote each, independently from one another,    linear or branched C1-C6-alkyl, wherein 1 to 5H atoms may be    replaced by Hal, OH and/or OAlk;-   R^(4a), R^(4b) denote each, independently from one another, H or    R^(3a);-   R⁵ denotes A1, Ar1, COA1, COAr1, SO₂A1, SO₂Ar1, and/or Het1;-   A1 denotes linear or branched C1-C6-alkyl, C3-C6-cycloalkyl, each    unsubstituted or mono-, di-, tri- or tetrasubstituted by Hal, CN,    R^(3a), SR^(3a), OR^(3a) and/or (CH₂)_(q)-A2;-   A2 denotes OH, OR^(3a);-   Alk denotes linear or branched C1-C6-alkyl;-   Ar1 denotes phenyl, which is unsubstituted, mono-, bi- or    trisubstituted by Hal, NO₂, CN, R^(3a), OR^(3a), CONHR^(3a),    NR^(3a)COR^(3b), SO₂R^(3a), SOR^(3a), NH₂, NHR^(3a), N(R^(3a))₂,    Ar2, Het2 and/or (CH₂)_(q)-A2;-   Het1 denotes saturated, unsaturated or aromatic 5- or 6-membered    heterocycle having 1 to 4 N, O and/or S atoms, wherein each    heterocycle may independently be unsubstituted or mono-, di-, tri-,    tetra- or pentasubstituted by Hal, NO₂, CN, R^(3a), OR^(3a),    CONHR^(3a), NR^(3a)COR^(3b), SO₂R^(3a), SOR^(3a), NH₂, NHR^(3a)    N(R^(3a))₂, Ar2, Het2 and/or (CH₂)_(q)-A2;-   Cyc denotes a mono- or bicyclic, 4-, 5-, 6-, 7-, 8-, 9- or    10-membered hydrocarbon or heterocycle, each independently from one    another unsubstituted or mono-, di-, tri-, tetra- or    pentasubstituted by Hal, CN, R^(3a), OR^(3a), CONR^(4a)R^(4b),    NR^(3a)COR^(3b)SO₂R^(3a), SOR^(3a), NR^(4a)R^(4b), Ar2, Het2,    (CH₂)_(q)—SR^(3a), (CH₂)_(q)—N(R^(3a))₂ and/or (CH₂)_(q)-A2, wherein    the monocyclic hydrocarbon system is aromatic and at least one ring    of the bicyclic hydrocarbon or heterocycle is aromatic, and wherein    the heterocyclic system contains 1, 2 or 3 N and/or O and/or S    atoms;-   Ar2 denotes phenyl, which is unsubstituted or mono- or disubstituted    by Hal, CN, R^(3a), OR^(3a), CONHR^(3a), NR^(3a)COR^(3b), SO₂R^(3a),    SOR^(3a), NH₂, NHR^(3a), N(R^(3a))₂ and/or (CH₂)_(q)-A2;-   Het2 denotes a saturated, unsaturated or aromatic 5- or 6-membered    heterocycle having 1 to 4 N, O and/or S atoms, which is    unsubstituted or mono- or disubstituted by Hal, CN, R^(3a), OR^(3a),    CONHR^(3a), NR^(3a)COR^(3b), SO₂R^(3a), SOR^(3a), NH₂, NHR^(3a),    N(R^(3a))₂ and/or (CH₂)_(q)-A2;-   n, q denote each, independently from one another, 1, 2, 3, 4, 5 or    6;-   m denotes 0, 1, 2, 3 or 4;-   Hal denotes F, Cl, Br or I;    and derivatives, prodrugs, solvates, tautomers or stereoisomers    thereof, as well as the physiologically acceptable salts of each of    the foregoing, including mixtures thereof in all ratios.

It is known that boronic acid derivatives such as compounds of formula(I), wherein R¹ and R² denote H form oligomers (Boronic Acids. Edited byDennis G. Hall, Copyright © 2005 WILEY-VCH Verlag, GmbH & Co. KGaA,Weinheim, ISBN 3-527-30991-8). Such oligomers (in particular but notlimited to dimers or trimers) of compounds of formula (I) are includedwithin this invention. Known cyclic trimers of boronic acids have forexample, the following structure:

It is to be noted that the compounds of the present invention bear astereogenic center at the carbon atom adjacent to the boronic acidresidue; it has been denoted with an asterisk (*) in formula (I)* below:

The compounds according to formula (I) thus exhibit two differentconfigurations at this stereogenic center, i.e. the (R)-configurationand the (S)-configuration. Hence, the compounds of the present inventionmay be present either enantiopure or as a racemic (1:1) mixture of thetwo enantiomers of formulas (R)-(Ia) and (S)-(Ia).

Compounds of formula (I) may also be present in a mixture in which oneof the enantiomers (R)-(Ia) or (S)-(Ia) is present in an excess over theother one, e.g. 60:40, 70:30, 80:20, 90:10, 95:5 or the like. In aparticular embodiment of the present invention the stereoisomer offormula (R)-(Ia) of the compound of formula (Ia) and the stereoisomer offormula (S)-(Ia) of the compound of formula (Ia) are present in a ratioof (R)-(Ia) to (S)-(Ia) of at least 90 parts of (R)-(Ia) to not morethan 10 parts of (S)-(Ia), preferably of at least 95 (R)-(Ia) to notmore than 5 (S)-(Ia), more preferably of at least 99 (R)-(Ia) to notmore than 1 (S)-(Ia), even more preferably of at least 99.5 (R)-(Ia) tonot more than 0.5 (S)-(Ia). In another particular embodiment of thepresent invention the stereoisomer of formula (S)-(Ia) of the compoundof formula (Ia) and the stereoisomer of formula (R)-(Ia) of the compoundof formula (Ia) are present in a ratio of (S)-(Ia) to (R)-(Ia) of atleast 90 (S)-(Ia) to not more than 10 (R)-(Ia), preferably of at least95 (S)-(Ia) to not more than 5 (R)-(Ia), more preferably of at least 99(S)-(Ia) to not more than 1 (R)-(Ia), even more preferably of at least99.5 (S)-(Ia) to not more than 0.5 (R)-(Ia).

Enriched or pure stereoisomers of formulas (R)-(Ia) and (S)-(Ia) can beobtained by usual methods known in the art and described hereinafter. Aparticular method for obtaining them is preparative columnchromatography, such as HPLC or SFC, using chiral column material.

In a particular preferred embodiment of the present invention thestereogenic center at the carbon atom adjacent to the boronic acidresidue shows an (R)-configuration as shown in as shown e.g. below:

The compounds according to formula (I) might also carry stereogeniccenters located a carbon atoms other than at the carbon atom adjacent tothe boronic acid residue. Such stereogenic centers may occur in (R)- or(S)-configuration.

Above and below, in those cases, where a chemical structure with astereogenic center is shown and no specific stereochemistry isindicated, the structures include all possible stereoisomers. Ingeneral, all residues of compounds described herein which occur morethan once may be identical or different, i.e. are independent of oneanother. Above and below, the residues and parameters have the meaningsindicated for formula (I), unless expressly indicated otherwise.Accordingly, the invention relates, in particular, to the compounds offormula (I) in which at least one of the said residues has one of thepreferred meanings indicated below. Furthermore, all specificembodiments described below shall include derivatives, prodrugs,solvates, tautomers or stereoisomers thereof as well as thephysiologically acceptable salts of each of the foregoing, includingmixtures thereof in all ratios.

In case Cyc denotes a bicyclic hydrocarbon or heterocycle, wherein atleast one of the two rings of is an aromatic ring, the other ring may bea saturated, unsaturated or aromatic ring. In specific embodiments thecovalent linkage between Cyc and the adjacent group LY occurs via the atleast one aromatic ring of Cyc. The bicyclic hydrocarbon or heterocycleis preferably 8-, 9- or 10-membered. Furthermore, in case Cyc is amonocyclic heterocycle it preferably contains 1, 2 or 3 heteroatomsselected from N, O and/or S, most preferably it contains 1 or 2heteroatoms. In case Cyc is a bicyclic heterocycle it preferablycontains 1, 2, 3 or 4 heteroatoms selected from N, O and/or S, mostpreferably it contains 1, 2 or 3 heteroatoms.

In case Cyc denotes a monocyclic, aromatic hydrocarbon system it ispreferably phenyl, which is unsubstituted or mono-, di- ortrisubstituted by Hal, CN, R^(3a), OR^(3a), CONR^(4a)R^(3a),NR^(3a)COR^(3b), SO₂R^(3a), SOR^(3a), NR^(4a)R^(3a), Ar2, Het2,(CH₂)_(q)—SR^(3a), (CH₂)_(q)—N(R^(3a))₂ and/or (CH₂)_(q)-A2.Particularly preferred are embodiments wherein Cyc denotes a di- ortrisubstituted phenyl. In those embodiments where Cyc denotes adisubstituted phenyl, the two substituents are preferably in 2,4- or3,4-position. And in those embodiments where Cyc denotes atrisubstituted phenyl, the three substituents are preferably in2,3,4-position of the aromatic ring.

In case Cyc denotes a monocyclic heterocycle this heterocycle can besaturated, unsaturated or aromatic.

One specific embodiment of the present invention comprises compounds offormula (I) wherein Y denotes Cyc and derivatives, prodrugs, solvates,tautomers or stereoisomers thereof, as well as the physiologicallyacceptable salts of each of the foregoing, including mixtures thereof inall ratios, wherein Cyc has the meaning as described above.

In such an embodiment Cyc may for example denote phenyl, 1- or2-naphthyl, 4- or 5-indanyl, 1-, 2-, 4-, 5- or 6-azulenyl, 1- or2-tetrahydronaphthalin 5- or 6-yl, 2- or 3-furyl, 2-, 3-, 4-, 5-, 6- or7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothiophenyl, benzodioxan-6- or7-yl or 3,4-dihydro-1,5-benzodioxepin-6- or -7-yl, each independentlyfrom one another unsubstituted or mono-, di-, tri-, tetra- orpentasubstituted by Hal, CN, R^(3a), OR^(3a), CONR^(4a)R^(4b),NR^(3a)COR^(3b), SO₂R^(3a), SOR^(3a), NR^(4a)R^(4b), (CH₂)_(q)—SR^(3a),(CH₂)_(q)—N(R^(3a))₂, Ar2, Het2 and/or (CH₂)_(q)-A2. In specificexamples of such an embodiment Cyc is unsubstituted or mono-, di- ortrisubstituted. Additionally, in case Cyc is substituted thesubstituents are preferably selected from a group comprising Hal,R^(3a), OR^(3a), Ar2, Het2. Thus, in such embodiments substituents ofCyc may e.g. be selected from a group consisting of F, Cl, Br, OCH₃,OC₂H₅, CH₂OCH₃, CH₃, C₂H₅, CF₃, OCF₃, phenyl, furyl, thienyl, pyrrolyl,imidazolyl, morpholinyl, piperazinyl, benzofuryl, benzodioxolyl and/orpyridyl or even more preferably selected from a group comprising F, Cl,Br, OCH₃, CH₂OCH₃, CH₃, C₂H₅, CF₃, OCF₃ and/or phenyl.

Another specific embodiment of the present invention comprises compoundsof formula (I) wherein:

-   R1, R2 denote H, C1-C4-alkyl (preferably methyl or ethyl) or R¹ and    R² form together a residue according to formula (CE)

and

-   X denotes 2-oxooxazolidinyl, 2-oxopyrrolidinyl, 2-oxopiperidyl,    3-oxomorpholinyl, 2-oxoazepanyl, 2-oxoimidazolidinyl,    2,5-dioxoimidazolidinyl, 2-oxooxazinanyl, 1,1-oxo-1,2-thiazinanyl,    thiazolidinoyl, isothiazolodinoyl, 2,4-dioxothiazolidinyl,    2-oxopiperazyl, 2,3-dioxopiperazyl, 2,6-dioxopiperidinyl,    2,6-dioxopyrrolidinyl or 2,4-dioxo-1,3-thiazolidinyl, each,    independently from each, other mono, di- or trisubstituted by A1,    Ar1, COA1, COAr1, SO₂A1, SO₂Ar1, and/or Het1;-   n,q denote each, independently from one another, 1, 2, 3 or 4; and-   m denotes 1 or 2;    and derivatives, prodrugs, solvates, tautomers or stereoisomers    thereof, as well as the physiologically acceptable salts of each of    the foregoing, including mixtures thereof in all ratios.

Furthermore, in such specific embodiments Ar1 preferably denotes phenyl,which is unsubstituted, mono-, bi- or trisubstituted by Hal, NO₂, CN,R^(3a), OR^(3a), CONHR^(3a)NR^(3a)COR^(3b), SO₂R^(3a), NH₂, NHR^(3a),N(R^(3a))₂, and/or (CH₂)_(q)-A2 (whereat most preferably substituentsare selected from Hal, R^(3a) and/or OR^(3a)); and Het1 preferablydenotes a saturated, unsaturated or aromatic 5- or 6-memberedheterocycle having 1, 2 or 3 (preferably 1 or 2) N, O and/or S atoms,which is unsubstituted or mono- or disubstituted by Hal, CN, R^(3a),OR^(3a), CONHR^(3a), NR^(3a)COR^(3b), SO₂R^(3a), SOR^(3a), NH₂,NHR^(3a), N(R^(3a))₂ and/or (CH₂)_(q)-A2 (whereat most preferablysubstituents are selected from Hal, R^(3a) and/or OR^(3a)).Additionally, in those cases where X as defined above is substituted byA1, Ar1 and/or Het1, the substituents may be attached to each atompossible.

Another specific embodiment of the present invention comprises compoundsof formula (I) wherein:

-   LX denotes (CH₂)_(n), wherein 1 to 5H atoms may be replaced by Hal,    R^(3a), OH, OR^(3a), phenyl, tolyl, ethylphenyl, fluorophenyl,    chlorophenyl, bromophenyl, aminophenyl, furyl, thienyl, pyrrolyl,    imidazolyl, pyrazolyl, pyrimidyl, morpholinyl and/or piperidinyl    and/or 1 CH₂ group may be replaced by O, SO or SO₂;-   LY denotes (CH₂)_(m), wherein 1 to 5H atoms may be replaced by Hal,    R^(3b), OR^(4b), and/or 1 CH₂ group may be replaced by O, SO or SO₂;-   Y denotes Cyc;-   R¹, R² denote each, independently from one another H, C-1-C4-alkyl    (preferably methyl or ethyl) or R¹ and R² form together a residue    according to formula (CE) as described above; and-   R^(3a), R^(3b) and R^(3c) denote each, independently from one    another, linear or branched C1-C4-alkyl, wherein 1 to 5H atoms may    be replaced by F, Cl, OH and/or OAlk;-   Alk denotes methyl or ethyl;-   X denotes 2-oxooxazolidinyl, 2-oxopyrrolidinyl, 2-oxopiperidyl,    3-oxomorpholinyl, 2-oxoazepanyl, 2-oxoimidazolidinyl,    2,5-dioxoimidazolidinyl, 2-oxooxazinanyl, 1,1-oxo-1,2-thiazinanyl,    thiazolidinoyl, isothiazolodinoyl, 2,4-dioxothiazolidinyl,    2-oxopiperazyl, 2,3-dioxopiperazyl, 2,6-dioxopiperidinyl,    2,6-dioxopyrrolidinyl or 2,4-dioxo-1,3-thiazolidinyl, each    independently from each other, unsubstituted or mono, di- or    trisubstituted by A1, Ar1, COA1, COAr1, SO₂A1, SO₂Ar1, and/or Het1;-   A1 denotes linear or branched C1-C6-alkyl, which is unsubstituted or    mono-, di- or trisubstituted by Hal, CN, R^(3a), OR^(3a), Ar2, Het2,    and/or (CH₂)_(q)-A2;-   Cyc denotes phenyl, which is unsubstituted, mono-, di- or    trisubstituted by Hal, CN, R^(3a), OR^(3a), CONR^(4a)R^(4b),    NR^(3a)COR^(3b), SO₂R^(3a), SOR^(3a), NR^(4a)R^(4b), Ar2, Het2    (CH₂)_(q)—SR^(3a), (CH₂)_(q)—N(R^(3a))₂ and/or (CH₂)_(q)-A2; wherein    in case of monosubstitution substituents are in 3- or 4-position,    and wherein in case of disubstitution substituents are in 2,4-, 2,5-    or 3,4-position and in case of trisubstitution substituents are in    2,3,4-position;    -   or    -   1- or 2-naphthyl, 4- or 5-indanyl, 1-, 2-, 4-, 5- or 6-azulenyl,        1- or 2-tetrahydronaphthalin 5- or 6-yl, 2- or 3-furyl, 2-, 3-,        4-, 5-, 6- or 7-benzofuryl, 2- or 3-thienyl, 1-, 2-, 3-, 4-, 5-,        6- or 7-indolyl, 2,3-dihydrobenzofuran-2- or 3-yl, 2-, 3-, 4-,        5-, 6- or 7-benzothiophenyl, benzodioxan-6- or 7-yl or        3,4-dihydro-1,5-benzo-dioxepin-6- or -7-yl, each independently        from one another, unsubstituted, mono-, disubstituted or        trisubstituted by Hal, CN, R^(3a), OR^(3a), CONR^(4a)R^(3a),        NR^(3a)COR^(3b), SO₂R^(3a), SOR^(3a), NR^(4a)R^(3a), Ar2, Het2,        (CH₂)_(q)—SR^(3a), (CH₂)_(q)—N(R^(3a))₂ and/or (CH₂)_(q)-A2;-   A2 OH, OCH₃, OCH₂CH₃, OCH(CH₃), OCF₃, OC₂F₅, O—CH₂—CH₂—OH or    O—CH₂—CH₂—OCH₃; and-   q,n denote each, independently from one another, 1, 2, 3 or 4; and-   m denotes 1 or 2;    and derivatives, prodrugs, solvates, tautomers or stereoisomers    thereof, as well as the physiologically acceptable salts of each of    the foregoing, including mixtures thereof in all ratios.    “Monosubstitution” means that the phenyl residue carries one    substituent other than H. Accordingly, “disubstitution” means that    the phenyl residue carries two substituents other than H and    “trisubstitution” means that the phenyl residue carries three    substituents other than H. Furthermore, in those specific    embodiments Ar1 and Het1 have preferably following meaning:-   Ar1 denotes phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-,    m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or    p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or    p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or    p-(N-methylamino)phenyl, o-, m- or p-(N-methylaminocarbonyl)phenyl,    o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or    p-ethoxyphenyl, o-, m- or p-(N,N-dimethylamino)phenyl, o-, m- or    p-(N-ethylamino)phenyl, o-, m- or p-(N,N-diethylamino)phenyl, o-, m-    or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or    p-chlorophenyl, o-, m- or p-(methylsulfonyl)phenyl, o-, m- or    p-methylsulfanylphenyl, o-, m- or p-cyanophenyl, o-, m- or    p-(3-oxomorpholin-4-yl)phenyl, o-, m- or p-(piperidinyl)phenyl, o-,    m- or p-(morpholin-4-yl)phenyl, furthermore preferably 2,3-, 2,4-,    2,5-, 2,6-, 3,4- or 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-    or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or    3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or    3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or    3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-,    2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro- or    2-amino-6-chlorophenyl, 2-nitro-4-N,N-dimethylamino- or    3-nitro-4-N,N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-,    2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl,    2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl,    3,6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl,    2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl,    3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl,    3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl,    3-amino-6-methylphenyl, 3-chloro-4-acetamidophenyl or    2,5-dimethyl-4-chlorophenyl;-   Het1 denotes 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl,    1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or    5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or    5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl,    furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl,    1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl,    1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,    1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,    1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl or pyrazinyl,    2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or    -5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl,    tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or    -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or    3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-,    -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl,    1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-,    -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or    4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxaneyl,    1,3-dioxane-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl,    hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl.

Further preferred embodiments of the present invention comprisecompounds of formula (I) wherein:

-   LX denotes —CH₂—, —CH₂—CH₂—, —CH₂—CH₂—CH₂—;-   LY denotes —CH₂— or —CH₂—CH₂—;-   Y denotes Cyc;-   R¹, R² denote each, independently from one another methyl or ethyl    or R¹ and R² form together a residue according to formula (CE) as    described above; and-   R^(3a), R^(3b) and R^(3c) denote methyl, ethyl, propyl, isopropyl,    CF₃, C₂F₅, CH₂OCH₃, CH₂OC₂H₅, CH₂OCH(CH₃)₂, C₂H₅OCH₃;-   X denotes 2-oxooxazolidinyl, 2-oxopyrrolidinyl, 2-oxopiperidyl,    3-oxomorpholinyl, 2-oxoazepanyl, 2-oxoimidazolidinyl,    2,5-dioxoimidazolidinyl, 2-oxooxazinanyl, 1,1-oxo-1,2-thiazinanyl,    thiazolidinoyl, isothiazolodinoyl, 2,4-dioxothiazolidinyl,    2-oxopiperazyl, 2,3-dioxopiperazyl, 2,6-dioxopiperidinyl,    2,6-dioxopyrrolidinyl or 2,4-dioxo-1,3-thiazolidinyl, each    independently from each other unsubstituted or mono or disubstituted    by A1 and/or Ar1;-   A1 denotes C1-C6-alkyl, preferably C1-C3-alkyl, each independently    from each other, unsubstituted or mono- or disubstituted by Hal, CN,    R^(3a), OR^(3a), Ar2, Het2, and/or (CH₂)_(q)-A2; most preferably A1    denotes unsubstituted C1-C3-alkyl;-   Ar1 denotes phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-,    m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or    p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or    p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or    p-(N-methylamino)phenyl, o-, m- or p-(N-methylaminocarbonyl)phenyl,    o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or    p-ethoxyphenyl, o-, m- or p-(N,N-dimethylamino)phenyl, o-, m- or    p-(N-ethylamino)phenyl, o-, m- or p-(N,N-diethylamino)phenyl, o-, m-    or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or    p-chlorophenyl, o-, m- or p-cyanophenyl, preferably 2,3-, 2,4-,    2,5-, 2,6-, 3,4- or 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-    or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or    3,5-dichlorophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or    3,4-dimethoxyphenyl,-   Cyc denotes phenyl, which is unsubstituted or mono-, di- or    trisubstituted by Hal, R^(3a), OR^(3a), wherein disubstitution is    preferably in 2,4-, 2,5- or 3,4-position and trisubstitution is in    2,3,4-position;    -   or    -   1- or 2-naphthyl, 2- or 3-thienyl, 3-benzofuryl or        2,3-dihydrobenzofuran-3-yl, each independently from one another,        unsubstituted, mono-, disubstituted or trisubstituted by Hal,        R^(3a), OR^(3a); and-   A2 OH, OCH₃, OCH₂CH₃, OCF₃, O—CH₂—CH₂—OH or O—CH₂—CH₂—OCH₃; and    and derivatives, prodrugs, solvates, tautomers or stereoisomers    thereof, as well as the physiologically acceptable salts of each of    the foregoing, including mixtures thereof in all ratios.

A specific embodiment of the invention comprises compounds according toformula (I), wherein Cyc denotes

-   -   2,4-, 3,4-, or 2,3,4-substituted phenyl or unsubstituted or        mono- or disubstituted 1- or 2-naphthyl, wherein the        substituents are each, independently from one another, selected        from a group consisting of Hal, CN, R^(3a), OR^(3a), CONHR^(3a),        CONR^(3b)R^(3a), CONH₂, NR^(3a)COR^(3b), SO₂R^(3a), SOR^(3a),        NHR^(3a), N(R^(3a))₂, (CH₂)_(q)—SR^(3a), (CH₂)_(q)—N(R^(3a))₂        and/or (CH₂)_(q)-A2;    -   or        Cyc is a residue according to formula (Fa7) or (Fb7)

wherein,

-   G^(a) denotes, F, Cl, Br, CN, R^(3a), OR^(3a), CONHR^(3a),    CONR^(3b)R^(3a), CONH₂, NR^(3a)COR^(3b), SO₂R^(3a), SOR^(3a),    NHR^(3a), N(R^(3a))₂, (CH₂)_(q)—SR^(3a), (CH₂)_(q)—N(R^(3a))₂ and/or    (CH₂)_(q)-A2;-   G^(b) denotes H, F, Cl, Br, CN, R^(3a), OR^(3a), CONHR^(3a),    CONR^(3b)R^(3a), CONH₂, NR^(3a)COR^(3b), SO₂R^(3a), SOR^(3a),    NHR^(3a), N(R^(3a))₂, (CH₂)_(q)—SR^(3a), (CH₂)_(q)—N(R^(3a))₂ and/or    (CH₂)_(q)-A2;-   K^(a), K^(b) denote each, independently from one another, H, F, Cl,    Br, CN, R^(3a), OR^(3a), CONHR^(3a), CONR^(3b)R^(3a), CONH₂,    NR^(3a)COR^(3b), SO₂R3a, SOR^(3a), NHR^(3a),    N(R^(3a))₂(CH₂)_(q)—SR^(3a), (CH₂)_(q)—N(R^(3a))₂ and/or    (CH₂)_(q)-A2;-   R^(3a), R^(3b) and R^(3c) denote each, independently from one    another, linear or branched C1-C3-alkyl, wherein 1 to 5H atoms may    be replaced by F, Cl, OH and OAlk, wherein Alk is methyl or ethyl;    -   q denotes 1 or 2        and derivatives, prodrugs, solvates, tautomers or stereoisomers        thereof, as well as the physiologically acceptable salts of each        of the foregoing, including mixtures thereof in all ratios.

The residue according to formula (Fb7) bears a stereogenic center at thecarbon atom next to LY; it has been denoted with an asterisk (*) informula (Fb7)* below:

The residues according to formula (Fb7) thus exhibit two differentconfigurations at this stereogenic center, i.e. the (R)-configurationand the (S)-configuration. Hence, the compounds of the present inventionmay be present either enantiopure or as a racemic (1:1) mixture of thetwo enantiomers of formulas (R)-(Fb7) and (S)-(Fb7).

Compounds of formula (I) which include residues according to formula(Fb7) may also be present in a mixture in which one of the enantiomers(R)-(Fb) or (S)-(Fb) is present in an excess over the other one, e.g.60:40, 70:30, 80:20, 90:10, 95:5 or the like. In a particular embodimentof the present invention the stereoisomer of formula (R)-(Fb7) of thecompound of formula (Ia) and the stereoisomer of formula (S)-(Fb7) ofthe compound of formula (Ia) are present in a ratio of (R)-(Fb7) to(S)-(Fb7) of at least 90 parts of (R)-(Fb7) to not more than 10 parts of(S)-(Fb7), preferably of at least 95 (R)-(Fb7) to not more than 5(S)-(Fb7), more preferably of at least 99 (R)-(Fb7) to not more than 1(S)-(Fb7), even more preferably of at least 99.5 (R)-(Fb7) to not morethan 0.5 (S)-(Fb7). In another particular embodiment of the presentinvention the stereoisomer of formula (S)-(Fb7) of the compound offormula (Fb7) and the stereoisomer of formula (R)-(Fb7) of the compoundof formula (I) are present in a ratio of (S)-(Fb7) to (R)-(Fb7) of atleast 90 (S)-(Fb7) to not more than 10 (R)-(Fb7), preferably of at least95 (S)-(Fb7) to not more than 5 (R)-(Fb7), more preferably of at least99 (S)-(Fb7) to not more than 1 (R)-(Fb7), even more preferably of atleast 99.5 (S)-(Fb7) to not more than 0.5 (R)-(Fb7).

In a preferred embodiment of the present invention, the stereogeniccenter at the carbon atom in position 3 of the dihydrofuranyl residueshows an (S)-configuration. Thus, the residue is a(3S)-2,3-dihydrobenzofuran-3-yl residue (S)-(Fb7):

Accordingly, in another very important embodiment of the invention thepresent invention comprises compounds according to formula (I), whichinclude a residue according to formula (Fb7), wherein the stereogeniccenter at the carbon atom in position 3 of the dihydrofuranyl residueshows an (S)-configuration and the stereogenic center at the carbon atomadjacent to the boronic acid residue shows an (R)-configuration:

A further embodiment of the invention comprises compounds according toformula (I), wherein Cyc denotes 2,4-, 3,4-, or 2,3,4-substituted phenylor unsubstituted or mono- or disubstituted 1- or 2-naphthyl, wherein thesubstituents are each, independently from one another, selected from agroup consisting of Hal, CN, R^(3a), OR^(3a), CONHR^(3a),CONR^(3b)R^(3a)CONH₂, NR^(3a)COR^(3b), SO₂R3a, SOR^(3a), NHR^(3a),N(R^(3a))₂, (CH₂)_(q)—SR^(3a), (CH₂)_(q)—N(R^(3a))₂ and/or (CH₂)_(q)-A2;

-   -   or        Cyc is a residue according to formula (Fa7) or (S)-(Fb7)

wherein,

-   G^(a) denotes F, Cl, Br, CN, R^(3a), OR^(3a), CONHR^(3a),    CONR^(3b)R^(3a), CONH₂, NR^(3a)COR^(3b) SO₂R^(3a), SOR^(3a),    NHR^(3a), N(R^(3a))₂, (CH₂)_(q)—SR^(3a), (CH₂)_(q)—N(R^(3a))₂ and/or    (CH₂)_(q)-A2;-   G^(b) denotes H, F, Cl, Br, CN, R^(3a), OR^(3a), CONHR^(3a),    CONR^(3b)R^(3a), CONH₂, NR^(3a)COR^(3b) SO₂R^(3a), SOR^(3a),    NHR^(3a), N(R^(3a))₂, (CH₂)_(q)—SR^(3a), (CH₂)_(q)—N(R^(3a))₂ and/or    (CH₂)_(q)-A2;-   K^(a), K^(b) denote each, independently from one another, H, F, Cl,    Br, CN, R^(3a), OR^(3a)CONHR^(3a), CONR^(3b)R^(3a), CONH₂,    NR^(3a)COR^(3b), SO₂R3a, SOR^(3a), NHR^(3a), N(R^(3a))₂,    (CH₂)_(q)—SR^(3a), (CH₂)_(q)—N(R^(3a))₂ and/or (CH₂)_(q)-A2;-   R^(3a), R^(3b) and R^(3c) denote each, independently from one    another, linear or branched C1-C3-alkyl, wherein 1 to 5H atoms may    be replaced by F, Cl, OH and OAlk, wherein Alk is methyl or ethyl;    -   q denotes 1 or 2        and derivatives, prodrugs, solvates, tautomers or stereoisomers        thereof, as well as the physiologically acceptable salts of each        of the foregoing, including mixtures thereof in all ratios.

A further specific embodiment of the invention comprises compoundsaccording to formula (I), wherein Cyc denotes

-   2,4-, 3,4-, or 2,3,4-substituted phenyl or unsubstituted or mono- or    disubstituted 1- or 2-naphthyl, wherein the substituents are each,    independently from one another, selected from a group consisting of    F, Cl, CH₃, C₂H₅, CF₃, OCH₃, OC₂H₅, COCF₃, SCH₃, SC₂H₅, CH₂OCH₃,    N(CH₃)₂, CH₂N(CH₃)₂ or N(C₂H₅)₂;    -   or    -   Cyc is a residue according to formula (Fa7), (Fb7) or (S)-(Fb7),        wherein-   G^(a) denotes F, Cl, CH₃, C₂H₅, CF₃, OCH₃, OC₂H₅, COCF₃, SCH₃,    SC₂H₅, CH₂OCH₃, N(CH₃)₂, CH₂N(CH₃)₂ or N(C₂H₅)₂;-   G^(b) denotes H, F, Cl, CH₃, C₂H₅, CF₃, OCH₃, OC₂H₅, COCF₃, SCH₃,    SC₂H₅, CH₂OCH₃, N(CH₃)₂, CH₂N(CH₃)₂ or N(C₂H₅)₂;-   K^(a), K^(b) denote each, independently from one another, H, F, Cl,    CH₃, C₂H₅, CF₃, OCH₃, OC₂H₅, COCF₃, SCH₃, SC₂H₅, CH₂OCH₃, N(CH₃)₂,    CH₂N(CH₃)₂ or N(C₂H₅)₂;    and derivatives, prodrugs, solvates, tautomers or stereoisomers    thereof, as well as the physiologically acceptable salts of each of    the foregoing, including mixtures thereof in all ratios.

Still a further specific embodiment of the invention comprises compoundsaccording to formula (I), wherein

-   LX denotes —CH₂—, —CH₂—CH₂—, —CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—,    —CH₂—CH₂—O—CH₂— wherein 1 to 4H atoms may be replaced by F or CI    and/or 1 or 2H atoms may be replaced by OH, methyl, ethyl,    isopropyl, CF₃, CF₂CF₃, OCH₃, OCH₂CH₃, O—CH₂—CH₂—OH, O—CH₂—CH₂—OCH₃,    phenyl, tolyl, ethylphenyl, fluoro-phenyl, chlorophenyl,    bromophenyl, aminophenyl, furyl, thienyl, pyrrolyl, imidazolyl,    pyrazolyl, pyrimidyl, morpholinyl and/or piperidinyl; and-   LY denotes —CH₂— or —CH₂—CH₂— wherein 1 to 4H atoms may be replaced    by F or C1 and/or 1 or 2H atoms may be replaced by OH, methyl,    ethyl, isopropyl, CF₃, CF₂CF₃, OCH₃, OCH₂CH₃, O—CH₂—CH₂—OH and/or    O—CH₂—CH₂—OCH₃; and-   Y denotes Cyc; and-   R¹, R² denote each, independently from one another H or C1-C4-alkyl,    or R¹ and R² form together a residue according to formula (CE) as    described above; and-   R^(3a), R^(3b) and R^(3c) denote each, independently from one    another, linear or branched C1-C3-alkyl, wherein 1 to 5H atoms may    be replaced by F, Cl, OH and OAlk, wherein Alk is methyl or ethyl;    and-   A denotes ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or    tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-,    1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or    4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl,    1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl or    1-ethyl-2-methylpropyl, each unsubstituted or mono-, di-, tri- or    tetrasubstituted by Hal, CN, R^(3a), SR^(3a), OR^(3a), Ar1, Het1,    and/or (CH₂)_(q)—Z; and-   Ar1 denotes phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-,    m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or    p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or    p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or    p-(N-methylamino)phenyl, o-, m- or p-(N-methylaminocarbonyl)phenyl,    o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or    p-ethoxyphenyl, o-, m- or p-(N,N-dimethylamino)phenyl, o-, m- or    p-(N-ethylamino)phenyl, o-, m- or p-(N,N-diethylamino)phenyl, o-, m-    or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or    p-chlorophenyl, o-, m- or p-(methylsulfonyl)phenyl, o-, m- or    p-methylsulfanylphenyl, o-, m- or p-cyanophenyl, o-, m- or    p-(3-oxomorpholin-4-yl)phenyl, o-, m- or p-(piperidinyl)phenyl, o-,    m- or p-(morpholin-4-yl)phenyl, furthermore preferably 2,3-, 2,4-,    2,5-, 2,6-, 3,4- or 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-    or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or    3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or    3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or    3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-,    2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro- or    2-amino-6-chlorophenyl, 2-nitro-4-N,N-dimethylamino- or    3-nitro-4-N,N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-,    2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl,    2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl,    3,6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl,    2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl,    3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl,    3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl,    3-amino-6-methylphenyl, 3-chloro-4-acetamidophenyl or    2,5-dimethyl-4-chlorophenyl; and-   Het1 denotes 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl,    1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or    5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or    5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl,    furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl,    1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl,    1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,    1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,    1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl or pyrazinyl,    2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or    -5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl,    tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or    -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or    3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-,    -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl,    1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-,    -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or    4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxaneyl,    1,3-dioxane-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl,    hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl;    and-   Cyc denotes 2,4-, 3,4-, or 2,3,4-substituted phenyl or unsubstituted    or mono- or disubstituted 1- or 2-naphthyl, wherein the substituents    are each, independently from one another, selected from a group    consisting of Hal, CN, R^(3a), OR^(3a)CONHR^(3a), CONR^(3b)R^(3a),    CONH₂, NR^(3a)COR^(3b), SO₂R3a, SOR^(3a), NHR^(3a), N(R^(3a))₂,    CH₂—Z, CH₂—SR^(3a), CH₂—N(R^(3a))₂,-   or-   a residue according to formula (Fa7) or (S)-(Fb7)

-   G^(a) denotes F, Cl, CH₃, C₂H₅, CF₃, OCH₃, OC₂H₅, COCF₃, SCH₃,    SC₂H₅, CH₂OCH₃, N(CH₃)₂, CH₂N(CH₃)₂ or N(C₂H₅)₂;-   G^(b) denotes H, F, Cl, CH₃, C₂H₅, CF₃, OCH₃, OC₂H₅, COCF₃, SCH₃,    SC₂H₅, CH₂OCH₃, N(CH₃)₂, CH₂N(CH₃)₂ or N(C₂H₅)₂;-   K^(a), K^(b) denote each, independently from one another, H, F, Cl,    CH₃, C₂H₅, CF₃, OCH₃, OC₂H₅, COCF₃, SCH₃, SC₂H₅, CH₂OCH₃, N(CH₃)₂,    CH₂N(CH₃)₂ or N(C₂H₅)₂;-   Z denotes OH, OCH₃, OCH₂CH₃, OCF₃, O—CH₂—CH₂—OH or O—CH₂—CH₂—OCH₃;-   q denotes 1, 2, 3 or 4;    and derivatives, prodrugs, solvates, tautomers or stereoisomers    thereof, as well as the physiologically acceptable salts of each of    the foregoing, including mixtures thereof in all ratios

In general, the residues included in formula (I) have preferably thefollowing meanings:

LX denotes preferably —CH₂—, —CH₂—CH₂—, —CH₂—CH₂—CH₂— or—CH₂—CH₂—CH₂—CH₂— wherein 1 to 4H atoms may be replaced by Hal and/or 1or 2H atoms may be replaced by R^(3a)Ar1 and/or Het1, and/or wherein 1or 2 non-adjacent CH₂ groups may be replaced by O, SO and/or SO₂.However, the maximum number of H atoms, which may be replaced is LX is5. Most preferably LX denotes —CH₂—, —CH₂—CH₂—, —CH₂—CH₂—CH₂—,—CH₂—CH₂—CH₂—CH₂—, —CH₂—CH₂—O—CH₂— wherein 1 to 4H atoms may be replacedby F or C1 and/or 1 or 2H atoms may be replaced by OH, methyl, ethyl,isopropyl, CF₃, CF₂CF₃, OCH₃, OCH₂CH₃, O—CH₂—CH₂—OH, O—CH₂—CH₂—OCH₃,phenyl, tolyl, ethylphenyl, fluorophenyl, chlorophenyl, bromophenyl,aminophenyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyrimidyl,morpholinyl and/or piperidinyl.

LY denotes preferably —CH₂—, —CH₂—CH₂— or —CH₂—CH₂—CH₂— wherein 1 to 4Hatoms may be replaced by Hal and/or 1H atom may be replaced by R^(3a),Ar1 and/or Het1, and/or wherein 1 or 2 non-adjacent CH₂ groups may bereplaced by O, SO and/or SO₂. However, the maximum number of H atoms,which may be replaced is LX is 5. Most preferably LY denotes —CH₂—,—CH₂—CH₂—, —CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—, —CH₂—CH₂—O—CH₂— wherein 1to 4H atoms may be replaced by F or C1 and/or 1 or 2H atoms may bereplaced by OH, methyl, ethyl, isopropyl, CF₃, CF₂CF₃, OCH₃, OCH₂CH₃,O—CH₂—CH₂—OH and/or O—CH₂—CH₂—OCH₃.

R¹, R² denote preferably each, independently from one another methyl,ethyl or R¹ and R² form together a residue according to formula (CE) asdescribed above.

R^(3a), R^(3b), R^(3e) denote preferably each, independently from oneanother, linear or branched C1-, C2- or C3-alkyl, wherein 1 to 5H atomsmay be replaced by F, Cl, OH and OAlk, wherein Alk is preferably methylor ethyl. Most preferably R^(3a), R^(3b), R^(3e) denote each,independently from one another, methyl, ethyl, (n-)propyl or iso-propyl,wherein one, two or three H atoms are replaced by F, Cl, OH, OCH₃ orOC₂H₅.

R^(4a) and R^(4b) denote preferably each, independently from oneanother, preferably H, methyl, furthermore ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl or pentyl, wherein 1, 2 or 3Hatoms are replaced by F, Cl, OH, OCH₃, OC₂H₅ or OCH(CH₃)₂.

R⁵ denotes preferably methyl, furthermore ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, COCH₃, SO₂CH₃, phenyl,tolyl ethylphenyl, fluorophenyl, chlorophenyl, bromophenyl, aminophenyl,furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyrimidyl, morpholinyland/or piperidinyl.

In embodiments where A1 is linear or branched C1-C6-alkyl it denotespreferably methyl, furthermore ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, 1-, 2- or 3-methylbutyl, 1,1-,1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, each unsubstituted or mono-, di- ortrisubstituted by Hal (preferably F or Cl), CN, R^(3a), OR^(3a)Ar2,Het2, and/or (CH₂)_(q)—Z. Most preferably A is selected from a groupconsisting of methyl, furthermore ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, 1-, 2- or 3-methylbutyl, 1,1-,1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl and 1,1,2-or 1,2,2-trimethylpropyl,

In embodiments where A1 is a cyclic alkyl group (cycloalkyl) itpreferably denotes cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,each unsubstituted or mono-, di- or trisubstituted by Hal (preferably For Cl), CN, R^(3a), OR^(3a), Ar2, Het2, and/or (CH₂)_(q)-A2. Mostpreferably it denotes cyclopropyl or cyclopentyl, each unsubstituted ormono- or di- by R^(3a) or Hal (preferably F or Cl). In specificembodiments A is unsubstituted cyclopropyl or cyclopentyl.

Ar1 can for example denote phenyl, o-, m- or p-tolyl, o-, m- orp-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl,o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- orp-nitrophenyl, o-, m- or p-aminophenyl, o-, m- orp-(N-methylamino)phenyl, o-, m- or p-(N-methylaminocarbonyl)phenyl, o-,m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- orp-ethoxyphenyl, o-, m- or p-(N,N-dimethyl-amino)phenyl, o-, m- orp-(N-ethylamino)phenyl, o-, m- or p-(N,N-diethylamino)phenyl, o-, m- orp-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-,m- or p-(methylsulfonyl)phenyl, o-, m- or p-methylsulfanylphenyl, o-, m-or p-cyanophenyl, o-, m- or p-(3-oxomorpholin-4-yl)phenyl, o-, m- orp-(piperidinyl)phenyl, o-, m- or p-(morpholin-4-yl)phenyl, o-, m- orp-trifluoromethyl-phenyl or o-, m- or p-trichloromethyl-phenyl,furthermore preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl,2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-,2,6-, 3,4- or 3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-,2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro- or2-amino-6-chlorophenyl, 2-nitro-4-N,N-dimethylamino- or3-nitro-4-N,N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-,2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl,2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl,3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl,3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.

Most preferably Ar1 denotes, phenyl which is unsubstituted, mono-, di ortrisubstituted by F, Cl, Br, OCH₃, CH₂OCH₃, CH₃, C₂H₅, CF₃, phenyl,biphenyl, naphthyl, furyl, thienyl, pyrrolyl, imidazolyl, morpholinyl,piperazinyl, benzofuryl, benzodioxolyl and/or pyridyl.

Het1 can for example denote 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-,4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl,furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-,-3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl,1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl,1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or4-pyridazinyl or pyrazinyl, each unsubstituted or mono-, di-, tri-,tetra- or pentasubstituted (preferably unsubstituted or mono-, di- ortrisubstituted) by Hal, CN, R^(3a), OR^(3a), CONHR^(3a)NR^(3a)COR^(3b),SO₂R^(3a), SOR^(3a), NH₂, NHR^(3a), N(R^(3a))₂, Ar2, Het2 and/or(CH₂)_(q)-A2. In such embodiments Het1 is most preferably unsubstitutedor mono-, di or trisubstituted (most preferably monosubstituted), by F,Cl, Br, OCH₃, CH₂OCH₃, CH₃, CF₃, phenyl, biphenyl, naphthyl, furyl,thienyl, pyrrolyl, imidazolyl, morpholinyl, piperazinyl, benzofuryl,benzodioxolyl and/or pyridyl.

However, Het1 may also be partially or fully hydrogenated. Thus, Het1can also denote, for example, 2,3-dihydro-2-, -3-, -4- or -5-furyl,2,5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or -3-furyl,1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-,-3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl,1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl,2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or-4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl,1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or-4-pyranyl, 1,4-dioxaneyl, 1,3-dioxane-2-, -4- or -5-yl, hexahydro-1-,-3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl or 1-,2- or 3-piperazinyl, each unsubstituted or mono-, di-, tri-, tetra- orpentasubstituted (preferably unsubstituted, mono-, di- ortrisubstituted) by Hal (preferably F or Cl), CN, R^(3a), OR^(3a),CONHR^(3a), NR^(3a)COR^(3b), SO₂R^(3a), SOR^(3a), NH₂, NHR^(3a),N(R^(3a))₂, Ar2, Het2 and/or (CH₂)_(q)-A2. In these embodiments Het1 ispreferably unsubstituted or mono-, di or trisubstituted (most preferablymonosubstituted), by F, Cl, Br, OCH₃, CH₂OCH₃, CH₃, CF₃, phenyl,biphenyl, naphthyl, furyl, thienyl, pyrrolyl, imidazolyl, morpholinyl,piperazinyl, benzofuryl, benzodioxolyl and/or pyridyl.

Cyc denotes preferably phenyl, 1- or 2-naphthyl, 4- or 5-indanyl, 1-,2-, 4-, 5- or 6-azulenyl, 1- or 2-tetrahydronaphthalin 5- or 6-yl, 2- or3-furyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or7-benzothiophenyl, 2methylenedioxyphenylbenzodioxan 6- or 7-yl or3,4-dihydro1,5-benzodioxepin-6- or -7-yl, each independently from oneanother unsubstituted, mono-, di- or trisubstituted by Hal (preferably For Cl), CN, R^(3a), OR^(3a)CONR^(4a)R^(4b), NR^(3a)COR^(3b), SO₂R^(3a),SOR^(3a), NR^(4a)R^(4b), Ar2, Het2 and/or (CH₂)_(q)-A2. Most preferablyCyc denotes phenyl, 4- or 5-indanyl, 1- or 2-naphthyl,1,2,3,4-tetrahydronaphthalin 5- or 6-yl, or 2-, 3-, 4-, 5-, 6- or7-benzofuranyl, each independently from one another, unsubstituted,mono-, disubstituted or trisubstituted by CH₃, C₂H₅, CH₂OCH₃, OCH₃, F,Cl, or CF₃. In case Cyc denotes a disubstituted phenyl the substituentsare preferably in 2,4-, 2,5- or 3,4-position, most preferably in 2,4- or3,4-position. In case Cyc denotes a trisubstituted phenyl thesubstituents are preferably in 2,3,4-position.

In particular Cyc can denote o-, m- or p-tolyl, o-, m- or p-ethylphenyl,o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- orp-tert-butylphenyl, o-, m- or p-acetamidophenyl, o-, m- orp-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-fluorophenyl, o-,m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- orp-trifluoromethyl-phenyl, o-, m- or p-trichloromethyl-phenyl, o-, m- orp-(methylsulfonyl)phenyl, o-, m- or p-phenoxyphenyl, o-, m- orp-methoxymethyl-phenyl further preferably 2,4-, 2,5-, 2,6- or 3,4-dimethylphenyl, 2,4-, 2,5- or 3,4-difluorophenyl, 2,4-, 2,5- or3,4-dichlorophenyl, 2,4-, 2,5- or 3,4-dibromophenyl, 2,5- or3,4-dimethoxyphenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or3,4,5-trichlorophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or3,4,5-trifluorophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or3,4,5-trimethylphenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or3,4,5-tris-trifluormethyl-phenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or3,4,5-tristrichlormethyl-phenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or3,4,5-trimethoxymethyl-phenyl, 2,4,6-trimethoxyphenyl, p-iodophenyl,2-fluoro-3-chlorophenyl, 2-fluoro-3-bromophenyl,2,3-difluoro-4-bromophenyl, 3-bromo-3-methoxyphenyl,2-chloro-3-methoxyphenyl, 2-fluoro-3-methoxyphenyl,2-chloro-3-acetamidophenyl, 2-fluoro-3-methoxyphenyl,2-chloro-3-acetamidophenyl, 2,3-dimethyl-4-chlorophenyl,2,3-dimethyl-4-fluorophenyl.

Cyc can also denote 1- or 2-naphthyl, 4- or 5-indanyl, 1-, 2-, 4-, 5- or6-azulenyl, 1- or 2-tetrahydronaphthalin 5- or 6-yl, 2- or 3-furyl, 2-,3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothiophenyl,methylenedioxy-phenylbenzodioxan-6- or 7-yl or3,4-dihydro-1,5-benzodioxepin-6- or -7-yl, each independently from oneanother unsubstituted or mono-, di- or trisubstituted by Hal, CN,R^(3a), OR^(3a), CONR^(4a)R^(4b), NR^(3a)COR^(3b), SO₂R^(3a), SOR^(3a),NR^(4a)R^(4b), Ar2, Het2 and/or (CH₂)_(q)-A2. Particularly preferredsubstituents of Cyc are selected from a group comprising Hal, CN,R^(3a), OR^(3a).

X denotes preferably 2-oxooxazolidinyl, 2-oxopyrrolidinyl,2-oxopiperidyl, 3-oxomorpholinyl, 2-oxoazepanyl, 2-oxoimidazolidinyl,2,5-dioxoimidazolidinyl, 2-oxooxazinanyl, 1,1-oxo-1,2-thiazinanyl,thiazolidinoyl, isothiazolodinoyl, 2,4-dioxothiazolidinyl,2-oxopiperazyl, 2,3-dioxopiperazyl, 2,6-dioxopiperidinyl,2,6-dioxopyrrolidinyl or 2,4-dioxo-1,3-thiazolidinyl, each independentlyfrom each other unsubstituted or mono or disubstituted COR^(3a), COAr²,SO₂R^(3a), SO₂Ar², A1, Ar1 and/or Het1. Most preferably substituents ofX are selected from a group consisting of methyl, ethyl, propyl,isopropyl, phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- orp-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- orp-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl,o-, m- or p-aminophenyl, o-, m- or p-(N-methylamino)phenyl, o-, m- orp-(N-methylaminocarbonyl)phenyl, o-, m- or p-acetamidophenyl, o-, m- orp-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- orp-(N,N-dimethyl-amino)phenyl, o-, m- or p-(N-ethylamino)phenyl, o-, m-or p-(N,N-diethylamino)phenyl, o-, m- or p-fluorophenyl, o-, m- orp-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-cyanophenyl, COCH₃,COC₆H₅, SO₂CH₃, SO₂C6H₅, COtolyl and SO₂tolyl.

Ar2 denotes preferably phenyl, which is unsubstituted or mono- ordisubstituted by Hal, CN, R^(3a), OR^(3a), CONHR^(3a), NH₂, NHR^(3a)and/or N(R^(3a))₂. Thus, Ar2 preferably denotes e.g. phenyl, o-, m- orp-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- orp-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- orp-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-,m- or p-(N-methylamino)phenyl, o-, m- orp-(N-methylaminocarbonyl)phenyl, o-, m- or p-acetamidophenyl, o-, m- orp-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- orp-(N,N-dimethylamino)phenyl, o-, m- or p-(N-ethylamino)phenyl, o-, m- orp-(N,N-diethylamino)phenyl, o-, m- or p-fluorophenyl, o-, m- orp-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-cyanophenyl.

Het2 denotes preferably a saturated, unsaturated or aromatic 5- or6-membered heterocycle having 1 to 4 N, O and/or S atoms, which isunsubstituted or mono- or disubstituted by Hal, CN, R^(3a), OR^(3a),CONHR^(3a), NH₂, NHR^(3a) and/or N(R^(3a))₂. Thus, Het2 may e.g. denote2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, imidazolyl, morpholinyl orpiperazinyl.

Alk denotes preferably methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl or tert-butyl, pentyl or hexyl, most preferablymethyl, ethyl, propyl or isopropyl.

A2 denotes preferably OH, methyl, ethyl, isopropyl, CF₃, CF₂CF₃, OCH₃,OCH₂CH₃, O—CH₂—CH₂—OH or O—CH₂—CH₂—OCH₃.

Hal denotes preferably F, Cl or Br, most preferably F or Cl.

n denotes preferably 1, 2, 3 or 4, more preferably n is 2, 3 or 4 andmost preferably n is 2 or 3.

m denotes preferably 0, 1 or 2, more 1 or 2 and most preferably 1.

q denotes preferably 1, 2, 3 or 4, more preferably n is 2, 3 or 4 andmost preferably n is 1,2 or 3.

In the context of the present invention “C1-C6-alkyl” means an alkylmoiety having 1, 2, 3, 4, 5 or 6 carbon atoms and being straight-chainor branched. The term “C1-C4-alkyl” means an alkyl moiety having 1, 2, 3or 4 carbon atoms and being straight-chain or branched. The term“C3-C6-cycloalkyl” refers to saturated cyclic hydrocarbon groups having3, 4, 5 or 6 carbon atoms.

The term “unsubstituted” means that the corresponding radical, group ormoiety has no substituents other than H; the term “substituted” meansthat the corresponding radical, group or moiety has one or moresubstituents. Where a radical has a plurality of substituents, i.e. atleast two, and a selection of various substituents is specified, thesubstituents are selected independently of one another and do not needto be identical.

Amino refers to the group —NRR′, wherein R and R′ are each independentlyfrom one another H or linear or branched C1-C6-alkyl (particularlymethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl ortert-butyl, pentyl, hexyl).

The group “CO” as e.g. included in the COR^(a), is group, wherein C andO are connected via a double bond (C═O).

Preferably, the compounds of the present invention are selected from thegroup consisting of:

and derivatives, prodrugs, solvates, tautomers or stereoisomers thereof,as well as the physiologically acceptable salts of each of theforegoing, including mixtures thereof in all ratios.

The invention further comprises a process for the preparation ofcompounds of the formula (I) as described above and pharmaceuticallyacceptable salts, tautomers and stereoisomers thereof, characterised inthat a compound of Formula (III)

is coupled with a compound of Formula (IV)

wherein all residues of formula (III) and formula (IV) are as definedabove, and wherein the obtained compound of Formula (Ib) is subsequentlyconverted into a compound of Formula (Ia), by treatment with HCl, HBr,HI and/or TFA, in the presence or absence of an excess of a smallmolecular weight boronic acid

In the process described above the reaction between the compound ofFormula (III) and the compound of Formula (IV) is preferably performedin the presence of a coupling agent selected from HATU, TBTU,polymer-supported 1-alkyl-2-chloropyridinium salt (polymer-supportedMukaiyama's reagent), 1-methyl-2-chloropyridinium iodide (Mukaiyama'sreagent), a carbodiimide.

The following abbreviations refer to the abbreviations used below:

ACN (acetonitrile), AcOH (acetic acid), BINAP(2,2′-bis(disphenylphosphino)-1,1′-binaphthalene), dba (dibenzylideneacetone), tBu (tert-Butyl), tBuOK (potassium tert-butoxide), CDI(1,1′-Carbonyldiimidazole), DBU (1,8-dizabicyclo[5.4.0]undec-7-ene), DCC(dicyclohexylcarbodiimide), DCM (dichloromethane), DIAD(diisobutylazodicarboxylate), DIC (diisopropylcarbodiimide), DIEA(di-isopropyl ethylamine), DMA (dimethyl acetamide), DMAP(4-dimethylaminopyridine), DMSO (dimethyl sulfoxide), DMF (N,N-dimethylformamide), EDC.HCl(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride), EtOAc(ethyl acetate), EtOH (ethanol), g (gram), cHex (cyclohexane), HATU(dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammoniumhexafluorophosphate), HOBt (N-hydroxybenzotriazole), HPLC (highperformance liquid chromatography), hr (hour), MHz (Megahertz), MeOH(methanol), min (minute), mL (milliliter), mmol (millimole), mM(millimolar), mp (melting point), MS (mass spectrometry), MW(microwave), NMM (N-methyl morpholine), NMR (Nuclear MagneticResonance), NBS (N-bromo succinimide), PBS (phosphate buffered saline),PMB (para-methoxybenzyl), PyBOP(benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate), RT(room temperature), TBAF (tetra-butylammonium fluoride), TBTU(N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate),T3P (propane phosphonic acid anhydride), TEA (triethyl amine), TFA(trifluoroacetic acid), THF (tetrahydrofuran), PetEther (petroleumether), TBME (tert-butyl methyl ether), TLC (thin layer chromatography),TMS (trimethylsilyl), TMSI (trimethylsilyl iodide), UV (ultraviolet).

Generally, compounds of Formula (I), wherein all residues are defined asabove, can be obtained from a compound of Formula (III) as outlined inScheme 1.

The first step consists of the reaction of a compound of Formula (III),wherein X and LX are defined as above, with a compound of Formula (IV),wherein R¹, R², LY and Y are defined as above. The reaction is performedusing conditions and methods well known to those skilled in the art forthe preparation of amides from a carboxylic acid with standard couplingagents, such as but not limited to HATU, TBTU, polymer-supported1-alkyl-2-chloropyridinium salt (polymer-supported Mukaiyama's reagent),1-methyl-2-chloropyridinium iodide (Mukaiyama's reagent), a carbodiimide(such as DCC, DIC, EDC) and HOBt, PyBOP® and other such reagents wellknown to those skilled in the art, preferably TBTU, in the presence orabsence of bases such as TEA, DIEA, NMM, polymer-supported morpholine,preferably DIEA, in a suitable solvent such as DCM, THF or DMF, at atemperature between −10° C. and 50° C., preferably at 0° C., for a fewhours, e.g. one hour to 24 h. Alternatively, the compounds of Formula(III) could be converted to carboxylic acid derivatives such as acylhalides or anhydrides, by methods well known to those skilled in theart, such as but not limited to treatment with SOCl₂, POCl₃, PCl₅,(COCl)₂, in the presence or absence of catalytic amounts of DMF, in thepresence or absence of a suitable solvent such as toluene, DCM, THF, ata temperature rising from 20° C. to 100° C., preferably at 50° C., for afew hours, e.g. one hour to 24 h. Conversion of the carboxylic acidderivatives to compounds of Formula (I), can be achieved usingconditions and methods well known to those skilled in the art for thepreparation of amides from a carboxylic acid derivative (e.g. acylchloride) with alkyl amines, in the presence of bases such as TEA, DIEA,NMM in a suitable solvent such as DCM, THF or DMF, at a temperaturerising from 20° C. to 100° C., preferably at 50° C., for a few hours,e.g. one hour to 24 h.

In the process described above the reaction between the compound ofFormula (III) and the compound of Formula (IV) is preferably performedin the presence of a coupling agent selected from HATU, TBTU,polymer-supported 1-alkyl-2-chloropyridinium salt (polymer-supportedMukaiyama's reagent), 1-methyl-2-chloropyridinium iodide (Mukaiyama'sreagent), a carbodiimide.

Compounds of Formula (Ia), wherein LX, X, LY and Y are defined as aboveand wherein R¹ and R² are H, can be prepared starting from compounds ofFormula (Ib), using methods well known to those skilled in the art forthe hydrolysis of boronic esters, such as but not limited to treatmentwith HCl, HBr, HI, TFA, in the presence or absence of an excess of asmall molecular weight boronic acid, such as but not limited toi-BuB(OH)₂ (Scheme 2).

Compounds of Formula (III) or (IV) are either commercially available orcan be prepared by methods well known to those skilled in the art.

In general, compounds of Formula (IV) are for example accessible by thefollowing Scheme 3a:

Compounds of formula (IV-1) wherein Y is a 2,3-dihydrobenzofuran-3-ylare for example accessible by the following Scheme 3b:

In this case typically both isomers at the 3 position of the2,3-dihydrobenzofurane are formed.

Amino boronic acids of formula IV-1a or IV-1b containingstereochemically pure 2,3-dihydrobenzofurane are accessible by thefollowing Scheme 4:

Compounds of formula I-1a and I-1b wherein Y is a2,3-dihydrobenzofuran-3-yl are for example accessible by the followingScheme 5:

The chiral separation can be performed e.g. by chiral HLPC.

Compounds of Formula (III) are for example accessible by the followingSchemes 4-1, 5-1, 6-1 or 7-1:

Alternatively compounds of formula (III) can be prepared usingalkylation reactions as key step, e.g.:

If the above set of general synthetic methods is not applicable toobtain compounds according to Formula (I) and/or necessary intermediatesfor the synthesis of compounds of Formula (I), suitable methods ofpreparation known by a person skilled in the art should be used.

In general, the synthesis pathways for any individual compounds offormula (I) will depend on the specific substituents of each moleculeand upon the ready availability of Intermediates necessary; again suchfactors being appreciated by those of ordinary skill in the art. For allthe protection and de-protection methods, see Philip J. Kocienski, in“Protecting Groups”, Georg Thieme Verlag Stuttgart, New York, 1994 and,Theodora W. Greene and Peter G. M. Wuts in “Protective Groups in OrganicSynthesis”, Wiley Interscience, 3rd Edition 1999.

Compounds of this invention can be isolated in association with solventmolecules by crystallization from evaporation of an appropriate solvent.The pharmaceutically acceptable acid addition salts of the compounds offormula (I), which contain a basic center, may be prepared in aconventional manner. For example, a solution of the free base may betreated with a suitable acid, either neat or in a suitable solution, andthe resulting salt isolated either by filtration or by evaporation undervacuum of the reaction solvent. Pharmaceutically acceptable baseaddition salts may be obtained in an analogous manner by treating asolution of compounds of formula (I), which contain an acid center, witha suitable base. Both types of salts may be formed or interconvertedusing ion-exchange resin techniques.

Depending on the conditions used, the reaction times are generallybetween a few minutes and 14 days, and the reaction temperature isbetween about −30° C. and 140° C., normally between −10° C. and 90° C.,in particular between about 0° C. and about 70° C.

Compounds of formula (I) can furthermore be obtained by liberatingcompounds of formula (I) from one of their functional derivatives bytreatment with a solvolysing or hydrogenolysing agent.

Preferred starting materials for the solvolysis or hydrogenolysis arethose which conform to formula (I), but contain corresponding protectedamino and/or hydroxyl groups instead of one or more free amino and/orhydroxyl groups, preferably those which carry an amino-protecting groupinstead of an H atom bound to an N atom, in particular those which carryan R′—N group, in which R′ denotes an amino-protecting group, instead ofan HN group, and/or those which carry a hydroxyl-protecting groupinstead of the H atom of a hydroxyl group, for example those whichconform to formula (I), but carry a —COOR″ group, in which R″ denotes ahydroxyl-protecting group, instead of a —COOH group.

It is also possible for a plurality of—identical or different—protectedamino and/or hydroxyl groups to be present in the molecule of thestarting material. If the protecting groups present are different fromone another, they can in many cases be cleaved off selectively.

The term “amino-protecting group” is known in general terms and relatesto groups which are suitable for protecting (blocking) an amino groupagainst chemical reactions, but which are easy to remove after thedesired chemical reaction has been carried out elsewhere in themolecule. Typical of such groups are, in particular, unsubstituted orsubstituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since theamino-protecting groups are removed after the desired reaction (orreaction sequence), their type and size are furthermore not crucial;however, preference is given to those having 1-20, in particular 1-8,carbon atoms. The term “acyl group” is to be understood in the broadestsense in connection with the present process. It includes acyl groupsderived from aliphatic, araliphatic, aromatic or heterocyclic carboxylicacids or sulfonic acids, and, in particular, alkoxy-carbonyl,aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of suchacyl groups are alkanoyl, such as acetyl, propionyl and butyryl;aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl and tolyl;aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxy-carbonyl,ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC(tert-butoxy-carbonyl) and 2-iodoethoxycarbonyl; aralkoxycarbonyl, suchas CBZ (“carbo-benz-oxy”), 4-methoxybenzyloxycarbonyl and FMOC; andaryl-sulfonyl, such as Mtr. Preferred amino-protecting groups are BOCand Mtr, furthermore CBZ, Fmoc, benzyl and acetyl.

The term “hydroxyl-protecting group” is likewise known in general termsand relates to groups which are suitable for protecting a hydroxyl groupagainst chemical reactions, but are easy to remove after the desiredchemical reaction has been carried out elsewhere in the molecule.Typical of such groups are the above-mentioned unsubstituted orsubstituted aryl, aralkyl or acyl groups, furthermore also alkyl groups.The nature and size of the hydroxyl-protecting groups are not crucialsince they are removed again after the desired chemical reaction orreaction sequence; preference is given to groups having 1-20, inparticular 1-10, carbon atoms. Examples of hydroxyl-protecting groupsare, inter alia, benzyl, 4-methoxybenzyl, p-nitro-benzoyl,p-toluenesulfonyl, tert-butyl and acetyl, where benzyl and tert-butylare particularly preferred.

The term “solvates of the compounds” is taken to mean adductions ofinert solvent molecules onto the compounds which form owing to theirmutual attractive force. Solvates are, for example, mono- or dihydratesor alcoholates.

The compounds of formula (I) are liberated from their functionalderivatives—depending on the protecting group used, for example, usingstrong acids, advantageously using TFA or perchloric acid, but alsousing other strong inorganic acids, such as hydrochloric acid orsulfuric acid, strong organic carboxylic acids, such as trichloroaceticacid, or sulfonic acids, such as benzene- or p-toluenesulfonic acid. Thepresence of an additional inert solvent is possible, but is not alwaysnecessary. Suitable inert solvents are preferably organic, for examplecarboxylic acids, such as acetic acid, ethers, such as THF or dioxane,amides, such as DMF, halogenated hydrocarbons, such as DCM, furthermorealso alcohols, such as methanol, ethanol or isopropanol, and water.Mixtures of the above-mentioned solvents are furthermore suitable. TFAis preferably used in excess without addition of a further solvent, andperchloric acid is preferably used in the form of a mixture of aceticacid and 70% perchloric acid at a ratio of 9:1. The reactiontemperatures for the cleavage are advantageously between about 0 andabout 50° C., preferably between 15 and 30° C. (RT).

The BOC, OBut and Mtr groups can, for example, preferably be cleaved offusing TFA in DCM or using approximately 3 to 5N HCl in dioxane at 15-30°C., and the FMOC group can be cleaved off using an approximately 5 to50% solution of dimethylamine, diethylamine or piperidine in DMF at15-30° C.

Protecting groups which can be removed hydrogenolytically (for exampleCBZ, benzyl or the liberation of the amidino group from the oxadiazolederivative thereof) can be cleaved off, for example, by treatment withhydrogen in the presence of a catalyst (for example a noble-metalcatalyst, such as palladium, advantageously on a support, such ascarbon). Suitable solvents here are those indicated above, inparticular, for example, alcohols, such as methanol or ethanol, oramides, such as DMF. The hydrogenolysis is generally carried out attemperatures between about 0 and 100° C. and pressures between about 1and 200 bar, preferably at 20-30° C. and 1-10 bar. Hydrogenolysis of theCBZ group succeeds well, for example, on 5 to 10% Pd/C in methanol orusing ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at20-30° C.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane,tri-fluoro-methyl benzene, chloroform or DCM; alcohols, such asmethanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol;ethers, such as diethyl ether, diisopropyl ether, tetrahydrofurane (THF)or dioxane; glycol ethers, such as ethylene glycol monomethyl ormonoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones,such as acetone or butanone; amides, such as acetamide,dimethylacetamide, N-methylpyrrolidone (NMP) or dimethyl-formamide(DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethylsulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formicacid or acetic acid; nitro compounds, such as nitromethane ornitrobenzene; esters, such as EtOAc, or mixtures of the said solvents.

Esters can be saponified, for example, using LiOH, NaOH or KOH in water,water/THF, water/THF/ethanol or water/dioxane, at temperatures between 0and 100° C. Furthermore, esters can be hydrolysed, for example, usingacetic acid, TFA or HCL.

Free amino groups can furthermore be acylated in a conventional mannerusing an acyl chloride or anhydride or alkylated using an unsubstitutedor substituted alkyl halide or reacted with CH3-C(═NH)—OEt,advantageously in an inert solvent, such as DCM or THF and/or in thepresence of a base, such as triethylamine or pyridine, at temperaturesbetween −60° C. and +30° C.

Throughout the specification, the term leaving group preferably denotesCl, Br, I or a reactively modified OH group, such as, for example, anactivated ester, an imidazolide or alkylsulfonyloxy having 1 6 carbonatoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) orarylsulfonyloxy having 6 10 carbon atoms (preferably phenyl- or ptolylsulfonyloxy).

Radicals of this type for activation of the carboxyl group in typicalacylation reactions are described in the literature (for example in thestandard works, such as Houben-Weyl, Methoden der organischen Chemie[Meth¬ods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart).

Activated esters are advantageously formed in situ, for example throughaddition of HOBt or N hydroxysuccinimide.

The term “pharmaceutically usable derivatives” is taken to mean, forexample, the salts of the compounds of the formula I and so-calledprodrug compounds.

The term “prodrug derivatives” is taken to mean compounds of the formulaI which have been modified with, for example, alkyl or acyl groups,sugars or oligopeptides and which are rapidly cleaved in the organism toform the active compounds.

These also include biodegradable polymer derivatives of the compoundsaccording to the invention, as described, for example, in Int. J. Pharm.115, 61-67 (1995).

The present invention relates to a process for making the compoundsaccording to Formula (I) and related Formulae.

The present invention relates to pharmaceutical compositions comprisingat least one compound of formula (I) wherein all residues are as definedabove, or its derivatives, prodrugs, solvates, tautomers orstereoisomers thereof as well as the physiologically acceptable salts ofeach of the foregoing, including mixtures thereof in all ratios, asactive ingredient, together with a pharmaceutically acceptable carrier.

For the purpose of the present invention the term “pharmaceuticalcomposition” refers to a composition or product comprising one or moreactive ingredients, and one or more inert ingredients that make up thecarrier, as well as any product which results, directly or indirectly,from combination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical compositions of the presentinvention encompass any composition made by admixing at least onecompound of the present invention and a pharmaceutically acceptablecarrier, excipient or vehicle. The pharmaceutical compositions of thepresent invention also encompass any composition that further comprisesa second active ingredient or its derivatives, prodrugs, solvates,tautomers or stereoisomers thereof as well as the physiologicallyacceptable salts of each of the foregoing, including mixtures thereof inall ratios, wherein that second active ingredient is other than acompound of formula (I) wherein all residues are defined above.

The invention relates to compounds according to formula (I) or anyspecific embodiment described above and pharmaceutically usable salts,tautomers, solvates and stereoisomers thereof, including mixturesthereof in all ratios, for use in the treatment and/or prophylaxis(prevention) of an immunoregulatory abnormality or hematologicalmalignancies.

For the purpose of the present invention immunoregulatory abnormality isan autoimmune or chronic inflammatory disease selected from the groupconsisting of systemic lupus erythematosus, chronic rheumatoidarthritis, inflammatory bowel disease, multiple sclerosis, amyotrophiclateral sclerosis (ALS), atherosclerosis, scleroderma, autoimmunehepatitis, Sjogren's syndrome, lupus nephritis, glomerulonephritis,Rheumatoid Arthritis, Psoriasis, Myasthenia Gravis, Immunoglobulin Anephropathy, Vasculitis, Transplant rejection, and asthma; and whereinthe hematological malignancy is a disease selected from the groupconsisting of Multiple myeloma, chronic lymphoid leukemia, acute myeloidleukemia, mantle cell lymphoma.

The invention relates to compounds according to formula (I) or anyspecific embodiment described above and their derivatives, prodrugs,solvates, tautomers or stereoisomers thereof as well as thephysiologically acceptable salts of each of the foregoing, includingmixtures thereof in all ratios, for use in the prevention and/ortreatment of medical conditions that are affected by inhibiting LMP7.The invention also relates to compounds according to formula (I) or anyspecific embodiment described above and its derivatives, prodrugs,solvates, tautomers or stereoisomers thereof as well as thephysiologically acceptable salts of each of the foregoing, includingmixtures thereof in all ratios, for use in the prevention and/ortreatment of an immunoregulatory abnormality or hematologicalmalignancies. In particular in such cases where the immunoregulatoryabnormality selected from Amyotrophic Lateral Sclerosis, Sjogren'ssyndrome, systemic lupus erythematoses, lupus nephritis,glomerulonephritis, Rheumatoid Arthritis, Inflammatory bowel disease,ulcerative colitis, Crohn's diseases, multiple sclerosis,osteoarthritis, Atherosclerosis, Psoriasis, Myasthenia Gravis, Dermalfibrosis, renal fibrosis, cardiac fibrosis, Liver fibrosis, Lungfibrosis, Immunoglobulin A nephropathy, Vasculitis, Transplantrejection, Hematological malignancies, Myositis, Henoch-SchonleinPurpura and asthma.

The pharmaceutical preparations can be employed as medicaments in humanand veterinary medicine.

The present invention further relates to a set (kit) consisting ofseparate packs of

-   -   (a) an effective amount of a compound of formula (I) and/or        pharmaceutically acceptable salts, tautomers and stereoisomers        thereof, including mixtures thereof in all ratios,    -   and    -   (b) an effective amount of a further medicament active        ingredient.

Pharmaceutical Salts and Other Forms

The said compounds of formula (I) can be used in their final non-saltforms. On the other hand, the present invention also relates to the useof these compounds in the form of their pharmaceutically acceptablesalts, which can be derived from various organic and inorganic acids andbases by procedures known in the art. Pharmaceutically acceptable saltforms of the compounds of formula (I) are for the most part prepared byconventional methods. If the compound of formula (I) contains an acidiccenter, such as a carboxyl group, one of its suitable salts can beformed by reacting the compound with a suitable base to give thecorresponding base-addition salt. Such bases are, for example, alkalimetal hydroxides, including potassium hydroxide and sodium hydroxide;alkaline earth metal hydroxides, such as magnesium hydroxide and calciumhydroxide; and various organic bases, such as piperidine,diethanolamine, N-methyl-glucamine (meglumine), benzathine, choline,ethylenediamine, benethamine, diethylamine, piperazine, lysine,L-arginine, ammonia, triethanolamine, betaine, ethanolamine, morpholineand tromethamine. In the case of certain compounds of formula (I), whichcontain a basic center, acid-addition salts can be formed by treatingthese compounds with pharmaceutically acceptable organic and inorganicacids, for example hydrogen halides, such as hydrogen chloride orhydrogen bromide, other mineral acids and corresponding salts thereof,such as sulfate, nitrate or phosphate and the like, and alkyl- andmonoaryl-sulfonates, such as methanesulfonate, ethanesulfonate,toluenesulfonate and benzene-sulfonate, and other organic acids andcorresponding salts thereof, such as carbonate, acetate,trifluoro-acetate, tartrate, maleate, succinate, citrate, benzoate,salicylate, ascorbate and the like. Accordingly, pharmaceuticallyacceptable acid-addition salts of the compounds of formula (I) includethe following: acetate, adipate, alginate, aspartate, benzoate,benzene-sulfonate (besylate), bisulfate, bisulfite, bromide, camphorate,camphor-sulfonate, caprate, caprylate, chloride, chlorobenzoate,citrate, cyclamate, cinnamate, digluconate, dihydrogen-phosphate,dinitrobenzoate, dodecyl-sulfate, ethanesulfonate, formate, glycolate,fumarate, galacterate (from mucic acid), galacturonate, glucoheptanoate,gluco-nate, glutamate, glycerophosphate, hemi-succinate, hemisulfate,heptanoate, hexanoate, hippurate, hydro-chloride, hydrobromide,hydroiodide, 2-hydroxy-ethane-sulfonate, iodide, isethionate,isobutyrate, lactate, lactobionate, malate, maleate, malonate,mandelate, metaphosphate, methanesulfonate, methylbenzoate,mono-hydrogen-phosphate, 2-naphthalenesulfonate, nicotinate, nitrate,oxalate, oleate, palmo-ate, pectinate, persulfate, phenylacetate,3-phenylpropionate, phosphate, phosphonate, phthalate, but this does notrepresent a restriction. Both types of salts may be formed orinterconverted preferably using ion-exchange resin techniques.

Furthermore, the base salts of the compounds of formula (I) includealuminum, ammonium, calcium, copper, iron (III), iron (II), lithium,magnesium, manganese (III), manganese (II), potassium, sodium and zincsalts, but this is not intended to represent a restriction. Of theabove-mentioned salts, preference is given to ammonium; the alkali metalsalts sodium and potassium, and the alkaline earth metal salts calciumand magnesium. Salts of the compounds of formula (I) which are derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary and tertiary amines, substituted amines, alsoincluding naturally occurring substituted amines, cyclic amines, andbasic ion exchange resins, for example arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzyl-ethylen-ediamine (benzathine),dicyclohexylamine, diethanol-amine, diethyl-amine,2-diethyl-amino-ethanol, 2-dimethyl-amino-ethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethyl-piperidine, glucamine,glucosamine, histidine, hydrabamine, isopropyl-amine, lido-caine,lysine, meglumine (N-methyl-D-glucamine), morpholine, piperazine,piperidine, polyamine resins, procaine, purines, theobromine,triethanol-amine, triethylamine, trimethylamine, tripropyl-amine andtris(hydroxy-methyl)-methylamine (tromethamine), but this is notintended to represent a restriction.

Compounds of formula (I) of the present invention which contain basicN2-containing groups can be quaternised using agents such as(C1-C4)-alkyl halides, for example methyl, ethyl, isopropyl andtert-butyl chloride, bromide and iodide; di(C1-C4)alkyl sulfates, forexample dimethyl, diethyl and diamyl sulfate; (C10-C18)alkyl halides,for example decyl, do-decyl, lauryl, myristyl and stearyl chloride,bromide and iodide; and aryl-(C1-C4)alkyl halides, for example benzylchloride and phenethyl bromide. Both water- and oil-soluble compounds offormula (I) can be prepared using such salts.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, me-glumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tro-meth-amine, but this is not intended to represent arestriction.

The acid-addition salts of basic compounds of formula (I) are preparedby bringing the free base form into contact with a sufficient amount ofthe desired acid, causing the formation of the salt in a conventionalmanner. The free base can be regenerated by bringing the salt form intocontact with a base and isolating the free base in a conventionalmanner. The free base forms differ from the corresponding salt formsthereof with respect to certain physical properties, such as solubilityin polar solvents; for the purposes of the invention, however, the saltsotherwise correspond to the respective free base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds of formula (I) are formed with metals or amines, such asalkali metals and alkaline earth metals or organic amines. Preferredmetals are sodium, potassium, magnesium and calcium. Preferred organicamines are N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanol-amine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base-addition salts of acidic compounds of formula (I) are preparedby bringing the free acid form into contact with a sufficient amount ofthe desired base, causing the formation of the salt in a conventionalmanner. The free acid can be regenerated by bringing the salt form intocontact with an acid and isolating the free acid in a conventionalmanner. The free acid forms differ from the corresponding salt formsthereof with respect to certain physical properties, such as solubilityin polar solvents; for the purposes of the invention, however, the saltsotherwise correspond to the respective free acid forms thereof.

If a compound of formula (I) contains more than one group which iscapable of forming pharmaceutically acceptable salts of this type,formula (I) also encompasses multiple salts. Typical multiple salt formsinclude, for example, bitartrate, diacetate, difumarate, dimeglumine,di-phosphate, disodium and trihydrochloride, but this is not intended torepresent a restriction.

With regard to that stated above, it can be seen that the term“pharmaceutically acceptable salt” in the present connection is taken tomean an active ingredient which comprises a compound of formula (I) inthe form of one of its salts, in particular if this salt form impartsimproved pharmacokinetic properties on the active ingredient comparedwith the free form of the active ingredient or any other salt form ofthe active ingredient used earlier. The pharmaceutically acceptable saltform of the active ingredient can also provide this active ingredientfor the first time with a desired pharmacokinetic property which it didnot have earlier and can even have a positive influence on thepharmacodynamics of this active ingredient with respect to itstherapeutic efficacy in the body.

Owing to their molecular structure, the compounds of formula (I) arechiral and can accordingly occur in various enantiomeric forms. They cantherefore exist in racemic or in optically active form.

Since the pharmaceutical activity of the racemates or stereoisomers ofthe compounds according to the invention may differ, it may be desirableto use the enantiomers. In these cases, the end product or even theIntermediates can be separated into enantiomeric compounds by chemicalor physical measures known to the person skilled in the art or evenemployed as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixtureby reaction with an optically active resolving agent. Examples ofsuitable resolving agents are optically active acids, such as the (R)and (S) forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaricacid, mandelic acid, malic acid, lactic acid, suitable N-protected aminoacids (for example N-benzoylproline or N-benzenesulfonylproline), or thevarious optically active camphorsulfonic acids. Also advantageous ischromatographic enantiomer resolution with the aid of an opticallyactive resolving agent (for example dinitrobenzoylphenylglycine,cellulose triacetate or other derivatives of carbohydrates or chirallyderivatised methacrylate polymers immobilised on silica gel). Suitableeluents for this purpose are aqueous or alcoholic solvent mixtures, suchas, for example, hexane/isopropanol/acetonitrile, for example in theratio 82:15:3.

The invention furthermore relates to the use of compounds of formula(I), and related formulae in combination with at least one furthermedicament active ingredient, preferably medicaments used in thetreatment of multiple sclerosis such as cladribine or another co-agent,such as interferon, e.g. pegylated or non-pegylated interferons,preferably interferon beta and/or with compounds improving vascularfunction or in combination with immunomodulating agents for exampleFingolimod; cyclosporins, rapamycins or ascomycins, or theirimmunosuppressive analogs, e.g. cyclosporin A, cyclosporin G, FK-506,ABT-281, ASM981, rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin etc.;corticosteroids; cyclophosphamide; azathioprene; methotrexate;leflunomide; mizoribine; mycophenolic add; mycophenolate mofetil;15-deoxyspergualine; diflucortolone valerate; difluprednate;Alclometasone dipropionate; amcinonide; amsacrine; asparaginase;azathioprine; basiliximab; beclometasone dipropionate; betamethasone;betamethasone acetate; betamethasone dipropionate; betamethasonephosphate sodium; betamethasone valerate; budesonide; captopril;chlormethine chlorhydrate; cladribine; clobetasol propionate; cortisoneacetate; cortivazol; cytarabine; daclizumab; dactinomycine; desonide;desoximetasone; dexamethasone; dexamethasone acetate; dexamethasoneisonicotinate; dexamethasone metasulfobenzoate sodium; dexamethasonephosphate; dexamethasone tebutate; dichlorisone acetate; doxorubicinechlorhydrate; epirubicine chlorhydrate; fluclorolone acetonide;fludrocortisone acetate; fludroxycortide; flumetasone pivalate;flunisolide; fluocinolone acetonide; fluocinonide; fluocortolone;fluocortolone hexanoate; fluocortolone pivalate; fluorometholone;fluprednidene acetate; fluticasone propionate; gemcitabine chlorhydrate;halcinonide; hydrocortisone, hydrocortisone acetate, hydrocortisonebutyrate, hydrocortisone hemisuccinate; melphalan; meprednisone;mercaptopurine; methylprednisolone; methylprednisolone acetate;methylprednisolone hemisuccinate; misoprostol; muromonab-cd3;mycophenolate mofetil; paramethasone acetate; prednazoline,prednisolone; prednisolone acetate; prednisolone caproate; prednisolonemetasulfobenzoate sodium; prednisolone phosphate sodium; prednisone;prednylidene; rifampicin; rifampicin sodium; tacrolimus; teriflunomide;thalidomide; thiotepa; tixocortol pivalate; triamcinolone; triamcinoloneacetonide hemisuccinate; triamcinolone benetonide; triamcinolonediacetate; triamcinolone hexacetonide; immunosuppressive monoclonalantibodies, e.g., monoclonal antibodies to leukocyte receptors, e.g.,MHC, CD2, CD3, CD4, CD7, CD25, CD28, B7, CD40, CD45 or CD58 or theirligands; or other immunomodulatory compounds, e.g. CTLA41g, or otheradhesion molecule inhibitors, e.g. mAbs or low molecular weightinhibitors including Selectin antagonists and VLA-4 antagonists. Apreferred composition is with Cyclosporin A, FK506, rapamycin or40-(2-hydroxy)ethyl-rapamycin and Fingolimod. These further medicaments,such as interferon beta, may be administered concomitantly orsequentially, e.g. by subcutaneous, intramuscular or oral routes.

These compositions can be used as medicaments in human and veterinarymedicine.

Pharmaceutical formulations can be administered in the form of dosageunits, which comprise a predetermined amount of active ingredient perdosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g,preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of acompound according to the invention, depending on the disease conditiontreated, the method of administration and the age, weight and conditionof the patient, or pharmaceutical formulations can be administered inthe form of dosage units which comprise a predetermined amount of activeingredient per dosage unit. Preferred dosage unit formulations are thosewhich comprise a daily dose or part-dose, as indicated above, or acorresponding fraction thereof of an active ingredient. Furthermore,pharmaceutical formulations of this type can be prepared using aprocess, which is generally known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active ingredient with the excipient(s) oradjuvant(s).

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Thus, for example, in the case of oral administration in the form of atablet or capsule, the active-ingredient component can be combined withan oral, non-toxic and pharmaceutically acceptable inert excipient, suchas, for example, ethanol, glycerol, water and the like. Powders areprepared by comminuting the compound to a suitable fine size and mixingit with a pharmaceutical excipient comminuted in a similar manner, suchas, for example, an edible carbohydrate, such as, for example, starch ormannitol. A flavour, preservative, dispersant and dye may likewise bepresent.

Capsules are produced by preparing a powder mixture as described aboveand filling shaped gelatine shells therewith. Glidants and lubricants,such as, for example, highly disperse silicic acid, talc, magnesiumstearate, calcium stearate or polyethylene glycol in solid form, can beadded to the powder mixture before the filling operation. A disintegrantor solubiliser, such as, for example, agar-agar, calcium carbonate orsodium carbonate, may likewise be added in order to improve theavailability of the medicament after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants anddisintegrants as well as dyes can likewise be incorporated into themixture. Suitable binders include starch, gelatine, natural sugars, suchas, for example, glucose or beta-lactose, sweeteners made from maize,natural and synthetic rubber, such as, for example, acacia, tragacanthor sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes,and the like. The lubricants used in these dosage forms include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride and the like. The disintegrants include,without being restricted thereto, starch, methylcellulose, agar,bentonite, xanthan gum and the like. The tablets are formulated by, forexample, preparing a powder mixture, granulating or dry-pressing themixture, adding a lubricant and a disintegrant and pressing the entiremixture to give tablets. A powder mixture is prepared by mixing thecompound comminuted in a suitable manner with a diluent or a base, asdescribed above, and optionally with a binder, such as, for example,carboxymethylcellulose, an alginate, gelatine or polyvinyl-pyrrolidone,a dissolution retardant, such as, for example, paraffin, an absorptionaccelerator, such as, for example, a quaternary salt, and/or anabsorbant, such as, for example, bentonite, kaolin or dicalciumphosphate. The powder mixture can be granulated by wetting it with abinder, such as, for example, syrup, starch paste, acacia mucilage orsolutions of cellulose or polymer materials and pressing it through asieve. As an alternative to granulation, the powder mixture can be runthrough a tableting machine, giving lumps of non-uniform shape which arebroken up to form granules. The granules can be lubricated by additionof stearic acid, a stearate salt, talc or mineral oil in order toprevent sticking to the tablet casting molds. The lubricated mixture isthen pressed to give tablets. The active ingredients can also becombined with a free-flowing inert excipient and then pressed directlyto give tablets without carrying out the granulation or dry-pressingsteps. A transparent or opaque protective layer consisting of a shellacsealing layer, a layer of sugar or polymer material and a gloss layer ofwax may be present. Dyes can be added to these coatings in order to beable to differentiate between different dosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can beprepared in the form of dosage units so that a given quantity comprisesa pre-specified amount of the compounds. Syrups can be prepared bydissolving the compounds in an aqueous solution with a suitable flavour,while elixirs are prepared using a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersion of the compounds in anon-toxic vehicle. Solubilisers and emulsifiers, such as, for example,ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,preservatives, flavour additives, such as, for example, peppermint oilor natural sweeteners or saccharin, or other artificial sweeteners andthe like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, beencapsulated in microcapsules. The formulation can also be prepared insuch a way that the release is extended or retarded, such as, forexample, by coating or embedding of particulate material in polymers,wax and the like.

The compounds of formula (I) and salts, solvates and physiologicallyfunctional derivatives thereof and the other active ingredients can alsobe administered in the form of liposome delivery systems, such as, forexam-pie, small unilamellar vesicles, large unilamellar vesicles andmultilamellar vesicles. Liposomes can be formed from variousphospholipids, such as, for example, cholesterol, stearylamine orphosphatidylcholines.

The compounds of formula (I) and the salts, solvates and physiologicallyfunctional derivatives thereof and the other active ingredients can alsobe delivered using monoclonal antibodies as individual carriers to whichthe compound molecules are coupled. The compounds can also be coupled tosoluble polymers as targeted medicament carriers. Such polymers mayencompass polyvinylpyrrolidone, pyran copolymer,polyhydroxypropyl-methacrylamidophenol,polyhydroxyethylaspartamidophenol or polyethylene oxide polylysine,substituted by palmitoyl radicals. The compounds may furthermore becoupled to a class of biodegradable polymers which are suitable forachieving controlled release of a medicament, for example polylacticacid, poly-epsilon-caprolactone, polyhydroxybutyric acid,poly-orthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylatesand crosslinked or amphipathic block copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration canbe administered as independent plasters for extended, close contact withthe epidermis of the recipient. Thus, for example, the active ingredientcan be delivered from the plaster by iontophoresis, as described ingeneral terms in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissue, for example mouthand skin, the formulations are preferably applied as topical ointment orcream. In the case of formulation to give an ointment, the activeingredient can be employed either with a paraffinic or a water-misciblecream base. Alternatively, the active ingredient can be formulated togive a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eyeinclude eye drops, in which the active ingredient is dissolved orsuspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouthencompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can beadministered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in whichthe carrier substance is a solid comprise a coarse powder having aparticle size, for example, in the range of 20-500 microns, which isadministered in the manner in which snuff is taken, i.e., by rapidinhalation via the nasal passages from a container containing the powderheld close to the nose. Suitable formulations for administration asnasal spray or nose drops with a liquid as a carrier substance encompassactive-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalationencompass finely particulate dusts or mists, which can be generated byvarious types of pressurised dispensers with aerosols, nebulisers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration can beadministered as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multidose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilised) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary.

Injection solutions and suspensions prepared in accordance with therecipe can be prepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavours.

A therapeutically effective amount of a compound of formula (I) and ofthe other active ingredient depends on a number of factors, including,for example, the age and weight of the animal, the precise diseasecondition which requires treatment, and its severity, the nature of theformulation and the method of administration, and is ultimatelydetermined by the treating doctor or vet. However, an effective amountof a compound is generally in the range of 0.1 to 100 mg/kg of bodyweight of the recipient (mammal) per day and particularly typically inthe range of 1 to 10 mg/kg of body weight per day. Thus, the actualamount per day for an adult mammal weighing 70 kg is usually between 70and 700 mg, where this amount can be administered as an individual doseper day or usually in a series of part-doses (such as, for example, two,three, four, five or six) per day, so that the total daily dose is thesame. An effective amount of a salt or solvate or of a physiologicallyfunctional derivative thereof can be determined as the fraction of theeffective amount of the compound per se.

The present invention furthermore relates to a method for treating asubject suffering from a sphingosine 1-phosphate associated disorder,comprising administering to said subject an effective amount of acompound of formula (I). The present invention preferably relates to amethod, wherein the sphingosine 1-phosphate associated disorder is anautoimmune disorder or condition associated with an overactive immuneresponse.

The present invention furthermore relates to a method of treating asubject suffering from an immunoregulatory abnormality or hematologicalmalignancy, comprising administering to said subject a compound offormula (I) in an amount that is effective for treating saidimmunoregulatory abnormality or hematological malignancies. The presentinvention preferably relates to a method wherein the immunoregulatoryabnormality is an autoimmune or chronic inflammatory disease.

EXAMPLES

¹HNMR:

Bruker 400 MHz

HPLC:

Method A

Method: A: 0.1% TFA in H₂O, B: 0.1% TFA in ACN: Flow 2.0 mL/min;Gradient: 0 min 5% B, 8.0 min: 100% B, 8.1 min: 100% B, 8.5 min: 5% B,10.0 min: 5% B.

Column: CBridge C8 (50×4.6 mm, 3.5 μm).

Method B

Method: 10 min 5-100% Acetonitril 0.05% TFA.

Column: CBridge C8 (50×4.6 mm, 3.5 μm).

Method C

Method: 10 min; 2 mL/min; 215 nm; Puffer A 0.05% TFA/H2O; Puffer B 0.04%TFA/ACN; 0.0-0.2 min 5% Puffer B; 0.2-8.5 min 5%-100% Puffer B; 8.5-10.0min 99%-5% Puffer B Column: CBridge C8-3.5 μm 4.6×502 mm.

Intermediate 1a: [(1R)-1-amino-2-(3-ethylbenzyl)boronicacid(+)-pinanediolester trifluoroacetate Step 1: (3-ethylphenyl)methanol

To a solution of 3-bromobenzylalcohol (10.00 g; 52.40 mmol; 1.00 eq.) inTHF (50.00 ml) taken in a pressure tube were added Cesium carbonate(51.73 g; 157.19 mmol; 3.00 eq.), Triethyl-borane (1.0 M in THF) (157.19ml; 157.19 mmol; 3.00 eq.) and1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.79 g; 1.05mmol; 0.02 eq.). The contents were heated at 70° C. for 5 h. TLC showedcompletion of reaction. The reaction mixture was cooled with ice andquenched with 100 mL of 10% NaOH solution, 20 mL of 30% H₂O₂ solution(added dropwise). The reaction mixture was further stirred at RT for 30minutes. The reaction mixture was cooled again, neutralized with conc.HCl and extracted with methyltertiarybutylether (MTBE). The organiclayer was dried over Na₂SO₄ and concentrated. The crude was purified bycolumn chromatography using 8% ethylacetate and petroleum ether toafford 3-Ethyl-phenyl)-methanol (7.00 g; 46.00 mmol; 87.8%; pale yellowliquid; Purified Product)

¹H NMR (400 MHz, CDCl₃): δ 7.32-7.28 (m, 1H), 7.23-7.13 (m, 3H), 4.97(s, 1H), 4.69 (s, 2H), 2.71-2.63 (m, 2H), 1.28-1.23 (m, 3H)

Step 2: 1-(bromomethyl)-3-ethylbenzene

A cold (0° C.) solution of (3-ethylphenyl) methanol (7.0 g, 46.0 mmol)in diethyl ether (70 mL) was treated with phosphorus tribromide (1.4 mL,15.2 mmol) and the reaction mixture was stirred at 0° C. for 30 min. Thereaction mixture was then poured into ice and extracted with ether. Theorganic layer was dried over sodium sulfate and concentrated. The crudeproduct (9.1 g, colorless liquid, 70.7%) was taken as such for next stepwithout purification.

¹H NMR (400 MHz, CDCl₃): δ 7.29-7.21 (m, 3H), 7.16-7.14 (m, 1H), 4.50(s, 2H), 2.69-2.64 (m, 2H), 1.28-1.24 (m, 3H)

Step 3: 2-(3-ethylbenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A solution of 1-(bromomethyl)-3-ethylbenzene (9.1 g, 32.5 mmol) indegassed 1, 4-dioxane (90 ml) was treated with bis(pinacolato)diboron(10.0 g, 39.0 mmol), potassium carbonate (13.6 g, 97.5 mmol),tetrakis(triphenylphosphine) palladium(0) (1.9 g, 1.6 mmol) and themixture heated at 100° C. for 12h The contents of the flask were cooledto room temperature and filtered through a celite bed. Filtrate wasconcentrated and the residue was dissolved in ethylacetate and washedwith brine. The organic layer was dried over sodium sulfate andconcentrated. The crude product was purified by Flash columnchromatography on silica gel, eluting with 2% of ethylacetate inpetroleum ether to get the title compound (8.7 g, 79%) as colourlessliquid.

¹H NMR (400 MHz, CDCl₃) b 7.19-7.15 (m, 1H), 7.03-6.96 (m, 3H),2.64-2.59 (m, 2H), 2.28 (s, 2H), 1.23 (s, 12H).

Step 4: 2-(3-ethylbenzyl)boronic acid (+)-pinanediol ester

A solution of 2-(3-ethylbenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(8.7 g, 28.0 mmol) in diethyl ether (90 ml) was treated with (1S, 2S,3R, 5S)-(+)-pinanediol (7.2 g, 42.0 mmol). The reaction mixture wasstirred at room temperature for 12 h then the mixture was washed withwater twice, then with brine and dried over anhydrous sodium sulphate,then concentrated. The crude product was purified by flash columnchromatography on silica gel, eluting with 3% of ethyl acetate inpetroleum ether, to afford the title compound (9.4 g, colourless liquid,88%).

¹H NMR (400 MHz, CDCl₃): δ 7.19-7.16 (m, 1H), 7.04-6.97 (m, 3H), 4.29(dd, J=1.88, 8.74 Hz, 1H), 2.65-2.59 (m, 2H), 2.35-2.31 (m, 3H),2.21-2.17 (m, 1H), 2.06 (t, J=5.84 Hz, 1H), 1.90-1.82 (m, 2H), 1.40 (s,3H), 1.29 (s, 3H), 1.10-1.07 (m, 1H), 0.84 (s, 3H). GCMS: m/z: 298.1.

Step 5: [(1S)-1-chloro-2-(3-ethylbenzyl)boronic acid (+)-pinanediolester

To a cooled (−100° C.) mixture of dichloromethane (3.1 ml, 48.0 mmol)and anhydrous tetrahydrofuran (40 ml) was added n-butyl lithium (1.6 Min hexanes, 11.0 ml, (17.6 mmol) over 20 min. After stirring for 20 min.at −100° C., a solution of 2-(3-ethylbenzyl)boronic acid (+)-pinanediolester (5.4 g, 16.0 mmol) in anhydrous THF (20 ml) was added over 20 min.Then a solution of zinc chloride (0.5 M in THF, 28.8 mL, 14.4 mmol) wasadded at −100° C. over 30 min. The mixture was allowed to reach roomtemperature and stirred for 18 h and concentrated. To the resulting oilwas added diethyl ether and saturated ammonium chloride. The organiclayer was dried over anhydrous sodium sulphate and concentrated invacuo. The residue (5.5 g, pale yellow oil, 99%) was taken as such forthe next step.

¹H NMR (400 MHz, CDCl₃): δ 7.23-7.21 (m, 1H), 7.11-7.07 (m, 3H), 4.36(dd, J=1.84, 8.80 Hz, 1H), 3.70-3.66 (m, 1H), 3.20-3.18 (m, 1H),3.13-3.11 (m, 1H), 2.67-2.61 (m, 2H), 2.35-2.34 (m, 1H), 2.18-2.16 (m,1H), 2.08 (t, J=5.96 Hz, 1H), 1.92-1.86 (m, 3H), 1.39 (s, 3H), 1.29 (s,3H), 1.26-1.22 (m, 3H), 1.11-1.08 (m, 1H), 0.85 (s, 3H). GCMS: m/z:346.2.

Step 6:[(1R)-1-[bis(trimethylsilyl)amino]-2-(3-ethylbenzyl)boronicacid(+)-pinanediolester

To a cooled (−78° C.) solution of [(1S)-1-chloro-2-(3-ethylbenzyl)boronic acid (+)-pinanediol ester (5.5 g,15.9 mmol) in 40 ml of anhydrous tetrahydrofuran was added lithiumbis(trimethylsilyl)amide (1M in THF, 19.8 ml, 19.8 mmol). The mixturewas allowed to attain room temperature, stirred for 18 h andconcentrated to dryness. To the resulting residue was added hexane, andthen the precipitated solid was filtered off. The filtrate wasconcentrated to give the required crude product (7.3 g, orange oil, 97%)which was taken as such for the next step without purification.

¹H NMR (400 MHz, CDCl₃): δ 7.18-7.16 (m, 1H), 7.10-7.05 (m, 2H),7.01-7.00 (m, 1H), 4.30 (dd, J=1.72, 8.72 Hz, 1H), 3.04-3.00 (m, 1H),2.84-2.83 (m, 1H), 2.67-2.60 (m, 3H), 2.35-2.33 (m, 1H), 2.14-2.12 (m,1H), 2.02 (t, J=5.80 Hz, 1H), 1.92-1.87 (m, 2H), 1.39 (s, 3H), 1.28 (s,3H), 1.26-1.22 (m, 3H), 1.00-0.97 (m, 1H), 0.85 (s, 3H), 0.09 (s, 18H).

Step 7: [(1R)-1-amino-2-(3-ethyl benzyl) boronicacid (+)-pinane diolester trifluoroacetate

A cooled (0° C.) solution of[(1R)-1-[bis(trimethylsilyl)amino]-2-(3-ethylbenzyl)boronic acid(+)-pinanediol ester (7.3 g, 15.5 mmol) in diethyl ether (35 ml) wastreated with trifluoroacetic acid (3.6 ml, 46.4 mmol) dropwise. Thereaction mixture was then stirred at RT for 3 h. Precipitation was seen.The reaction mixture was cooled to 0° C. and filtered. The filteredsolid was washed with cold ether and dried under vacuum to afford thetitle compound (2.8 g, white solid, 41%).

¹H NMR (400 MHz, CDCl₃): δ 7.78 (s, 3H), 7.26-7.22 (m, 1H), 7.12-7.09(m, 3H), 4.31 (dd, J=1.80, 8.68 Hz, 1H), 3.20-3.11 (m, 2H), 3.05-2.99(m, 1H), 2.65-2.59 (m, 2H), 2.24-2.17 (m, 2H), 1.96 (t, J=5.68 Hz, 1H),1.90-1.88 (m, 1H), 1.85-1.80 (m, 1H), 1.33 (s, 3H), 1.26 (s, 3H), 1.23(t, J=7.60 Hz, 3H), 1.06-1.03 (m, 1H), 0.80 (s, 3H).

Intermediate 1b: 2-(7-Methyl-benzofuran-3-yl)-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylaminehydrochloride Step 1: 7-Methyl-benzofuran-3-carboxylic acid ethyl ester

To a solution of 2-Hydroxy-3-methyl-benzaldehyde (20.00 g; 139.55 mmol;1.00 eq.) in dichloromethane (120 mL) was added Tetrafluoroboric aciddiethyl ether complex (1.88 ml; 13.96 mmol; 0.10 eq.). To the resultingdark red mixture, Ethyldiazoacetate (31.70 ml; 300.04 mmol; 2.15 eq.) indichloromethane (80 mL) was added drop wise slowly at 25-30° C.(internal temperature) for about 50 min. (note: evolution of N₂ wasobserved). After 16 h, concentrated H₂SO₄ was added. The reactionmixture was stirred for 30 min. The reaction mixture was thenneutralized with solid NaHCO₃, filtered through celite and the filtratewas concentrated to get a crude residue. The residue was purified bycolumn chromatography using 2% ethyl acetate in petroleum ether toafford 7-Methyl-benzofuran-3-carboxylic acid ethyl ester (19.00 g; 86.83mmol; 62.2%; yellow oil; Purified Product).

HPLC (method A): RT 4.98 min (HPLC purity 93%)

¹H NMR, 400 MHz, CDCl₃: 8.27 (s, 1H), 7.88-7.90 (m, 1H), 7.25-7.29 (m,1H), 7.17 (d, J=7.32 Hz, 1H), 4.39-4.45 (m, 2H), 2.55 (s, 3H), 1.44 (t,J=7.16 Hz, 3H).

Step 2: (7-Methyl-benzofuran-3-yl)-methanol

To a solution of 7-Methyl-benzofuran-3-carboxylic acid ethyl ester(19.00 g; 86.83 mmol; 1.00 eq.) in Dichloromethane (190.00 ml; 10.00 V)under nitrogen was added Diisobutyl Aluminium Hydride (1.0 M in Toluene)(191.03 ml; 191.03 mmol; 2.20 eq.) drop wise at −78° C. The reactionmixture was allowed to come to RT and stirred for 1 h. The reactionmixture was cooled with ice bath and quenched with an aqueous solutionof 1.5N HCl. The resultant mixture (which had sticky solid masssuspended in solvent) was diluted with ethylacetate and filtered throughcelite. The celite bed was washed thoroughly with ethylacetate anddichloromethane. The filtrate was evaporated to get a crude residue. Thesolid which remained in the celite bed was taken and triturated withethylacetate and filtered. The filtrate was mixed together with thecrude residue and evaporated. The residue thus obtained was taken inethylacetate and washed with an aqueous solution of 1.5 N HCl and brine.The organic layer was dried over anhydrous Na₂SO₄ and concentrated. Theresidue obtained was purified by flash column chromatography using40-50% ethyl acetate in petroleum ether as eluent to get(7-Methyl-benzofuran-3-yl)-methanol (8.20 g; 48.40 mmol; 55.7%; lightyellow oil; Purified Product).

HPLC (Method A): RT 3.33 min, (HPLC purity 95.7%).

¹H NMR, 400 MHz, CDCl₃: 7.64 (s, 1H), 7.50-7.52 (m, 1H), 7.17-7.21 (m,1H), 7.14 (d, J=7.20 Hz, 1H), 4.86-4.86 (m, 2H), 2.54 (s, 3H).

Step 3: 3-(bromomethyl)-7-methyl-benzofuran

To an ice-cooled solution of (7-Methyl-benzofuran-3-yl)-methanol (8.20g; 48.40 mmol; 1.00 eq.) in Diethyl ether (82.00 ml; 10.00 V) undernitrogen atmosphere was added phosphorus tribromide (1.53 ml; 16.12mmol; 0.33 eq.) drop wise and the reaction mixture was stirred at icecold condition for 30 minutes. The reaction mixture was poured into iceand extracted with diethyl ether. The organic layer was dried overanhydrous Na₂SO₄ and concentrated to afford3-Bromomethyl-7-methyl-benzofuran (10.00 g; 44.43 mmol; 91.8%; colorlessoil). The crude product was taken to next step without purification.

¹H NMR, 400 MHz, CDCl₃: 7.71 (s, 1H), 7.53-7.55 (m, 1H), 7.21-7.25 (m,1H), 7.16 (d, J=7.32 Hz, 1H), 4.65 (s, 2H), 2.48 (s, 3H).

Step 4:7-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-ylmethyl)-benzofuran

To a solution of 3-Bromomethyl-7-methyl-benzofuran (10.00 g; 44.43 mmol;1.00 eq.) in degassed Dioxane-1,4 (100.00 ml; 10.00 V) were addedBis(pinacolato)diboron (13.68 g; 53.31 mmol; 1.20 eq.), dried K₂CO₃(18.61 g; 133.28 mmol; 3.00 eq.) andtetrakis(triphenylphosphine)palladium(0) (2.57 g; 2.22 mmol; 0.05 eq.).The reaction mixture was then heated at 100° C. under nitrogenatmosphere for 16 h. The reaction mixture was diluted withdichloromethane and filtered through celite. The filtrate wasconcentrated. The residue was dissolved in ethyl acetate and washed withbrine. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated. The crude was purified by column chromatography using 2%ethyl acetate in petroleum ether to get7-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-ylmethyl)-benzofuran(5.00 g; 18.37 mmol; 41.4%; colorless liquid; Purified Product).

¹H NMR, 400 MHz, DMSO-d6: 7.65 (s, 1H), 7.33-7.35 (m, 1H), 7.07-7.13 (m,2H), 2.43 (s, 3H), 2.13 (s, 2H), 1.16 (s, 12H).

Step 5:Trimethyl-4-(7-methyl-benzofuran-3-ylmethyl)-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]decane

To an ice-cooled solution of7-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-ylmethyl)-benzofuran(5.00 g; 18.37 mmol; 1.00 eq.) in Et₂O (50.00 ml; 10.00 V) undernitrogen atmosphere was added 1S, 2S, 3R, 5S-(+)-2,3-pinane diol (4.69g; 27.56 mmol; 1.50 eq.) and the reaction mixture was stirred at RT for14 h. TLC analysis showed completion of reaction. The reaction mixturewas washed with brine. The organic layer was dried over anhydrous Na₂SO₄and concentrated. The crude was purified by flash column chromatographyusing 2% ethyl acetate in petroleum ether to get (1S,2S,6R,8S)-2,9,9-Trimethyl-4-(7-methyl-benzofuran-3-ylmethyl)-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]decane (5.00 g; 13.00 mmol; 70.7%; colorless liquid; Purified Product).

GCMS: m/z: 324.2

¹H NMR, 400 MHz, CDCl₃: 7.53-7.55 (m, 1H), 7.39-7.40 (m, 1H), 7.12-7.27(m, 1H), 7.06-7.08 (m, 1H), 4.31-4.34 (m, 1H), 2.53 (s, 3H), 2.30-2.37(m, 1H), 2.26 (s, 2H), 2.18-2.23 (m, 1H), 2.07 (t, J=5.76 Hz, 1H),1.84-1.93 (m, 2H), 1.42 (s, 3H), 1.29 (s, 3H), 1.12-1.15 (m, 1H), 0.85(s, 3H).

Step 6: (1S,2S,6R,8S)-4-[1-Chloro-2-(7-methyl-benzofuran-3-yl)-ethyl]-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]decane

Dichloromethane (2.96 ml; 46.26 mmol; 3.00 eq.) in THF (40 mL) was takenin a RB-flask under a positive pressure of nitrogen and cooled to −95°C. using liquid nitrogen-ethanol mixture. To this n-butyl lithium (1.6 Min hexanes) (10.60 ml; 16.96 mmol; 1.10 eq.) was added drop wise throughthe sides of the RB-flask (at a medium rate, addition took about 30min.) so that the internal temperature was maintained between −95° C.and −100° C. After addition, the reaction mixture was stirred for 20minutes. During the course of the reaction a white precipitate wasformed (the internal temperature was maintained between −95° C. and−100° C.). Then a solution of(1S,2S,6R,8S)-2,9,9-Trimethyl-4-(7-methyl-benzofuran-3-ylmethyl)-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]decane(5.00 g; 15.42 mmol; 1.00 eq.) in THF (20 mL) was added drop wisethrough the sides of the RB-flask (about 25 min) so that the internaltemperature was maintained between −95° C. and −100° C. After addition,immediately zinc chloride (0.5 M in THF) (27.76 ml; 13.88 mmol; 0.90eq.) was added drop wise through the sides of the RB-flask (at a mediumrate, addition took about 45 min.) so that the internal temperature wasmaintained between −95° C. and −100° C. The reaction mixture was thenslowly allowed to attain RT and stirred at RT for 16 h. The reactionmixture was concentrated (temperature of the bath 30° C.). The residuewas partitioned between diethyl ether and saturated NH₄Cl solution. Theorganic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated (temperature of bath 30° C.) to afford(1S,2S,6R,8S)-4-[1-Chloro-2-(7-methyl-benzofuran-3-yl)-ethyl]-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]decane(5.90 g; 15.83 mmol; 102.7%; brown liquid; Crude Product).

¹H NMR, 400 MHz, CDCl₃: 7.57 (s, 1H), 7.42-7.44 (m, 1H), 7.27 (s, 1H),7.09-7.18 (m, 1H), 4.34-4.36 (m, 1H), 3.74-3.76 (m, 1H), 3.28-3.30 (m,1H), 3.20-3.22 (m, 1H), 2.52 (s, 3H), 2.32-2.34 (m, 1H), 2.07 (t, J=5.88Hz, 1H), 1.85-1.91 (m, 2H), 1.42 (s, 3H), 1.29 (s, 3H), 1.06-1.09 (m,1H), 0.85 (s, 3H).

Step 7:((1S,2S,6R,8S)-4-[1-(1,1,1,3,3,3-Hexamethyl-disilazan-2-yl)-2-(7-methyl-benzofuran-3-yl)-ethyl]-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]decane

A solution of(1S,2S,6R,8S)-4-[1-Chloro-2-(7-methyl-benzofuran-3-yl)-ethyl]-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]decane(5.90 g; 15.83 mmol; 1.00 eq.) in THF (40.00 ml; 6.78 V) under apositive pressure of nitrogen atmosphere was cooled to −78° C. To this asolution of lithium (bistrimethylsilyl)amide (1.0 M in THF) (17.41 ml;17.41 mmol; 1.10 eq.) was added drop wise over a period of 30 minutes.The reaction mixture was allowed to attain RT and stirred at RT for 18h. The reaction mixture was evaporated at 30° C. The residue wastriturated with n-hexane and the solid formed was filtered. The filtratewas concentrated at 30° C. to get(1S,2S,6R,8S)-4-[1-(1,1,1,3,3,3-Hexamethyl-disilazan-2-yl)-2-(7-methyl-benzofuran-3-yl)-ethyl]-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]decane(6.00 g; 12.06 mmol; 76.2%; brown dark oil; Crude Product).

The crude product was taken to next step without purification. Theproduct was confirmed by ¹H-NMR and was unstable in LCMS conditions.

¹H NMR, 400 MHz, CDCl₃: 7.50 (s, 1H), 7.41-7.43 (m, 1H), 7.12-7.16 (m,1H), 7.06-7.08 (m, 1H), 4.29-4.32 (m, 1H), 3.17-3.09 (m, 1H), 2.70-2.89(m, 1H), 2.52-2.70 (m, 1H), 2.52 (s, 3H), 2.28-2.31 (m, 1H), 2.14-2.14(m, 1H), 2.03 (t, J=5.68 Hz, 1H), 1.78-1.89 (m, 2H), 1.39 (s, 3H), 1.31(s, 3H), 1.01-1.04 (m, 1H), 0.90-0.92 (m, 2H), 0.88 (s, 3H), 0.12 (s,18H).

Step 8: 2-(7-Methyl-benzofuran-3-yl)-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylaminehydrochloride

A stirred solution of(1S,2S,6R,8S)-4-[1-(1,1,1,3,3,3-Hexamethyl-disilazan-2-yl)-2-(7-methyl-benzofuran-3-yl)-ethyl]-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]decane(6.00 g; 12.06 mmol; 1.00 eq.) in Diethyl ether (60.00 ml; 10.00 V)under nitrogen atmosphere was cooled to −10° C. To this 2M solution ofHydrochloric acid in diethyl ether (15.07 ml; 30.14 mmol; 2.50 eq.) wasadded drop wise. The reaction mixture was stirred at RT for 2 h. Thereaction mixture was evaporated at 30° C. To the residue diethyl ether(20 mL) was added and the solid formed was filtered off, washed withcold diethyl ether and dried under vacuum to get2-(7-Methyl-benzofuran-3-yl)-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylaminehydrochloride (3.50 g; 8.98 mmol; 74.5%; brown orange solid; CrudeProduct).

¹H NMR, 400 MHz, DMSO-d6: 8.09 (s, 3H), 7.83 (s, 1H), 7.52-7.53 (m, 1H),7.12-7.19 (m, 2H), 4.39 (dd, J=1.84, 8.62 Hz, 1H), 3.07-3.13 (m, 1H),3.03-3.07 (m, 2H), 2.43 (s, 4H), 2.28-2.30 (m, 1H), 2.07-2.08 (m, 1H),1.92 (t, J=5.68 Hz, 1H), 1.82-1.84 (m, 1H), 1.71-1.75 (m, 1H), 1.19-1.25(m, 8H), 1.00-1.08 (m, 1H), 0.78 (s, 3H).

Intermediate 1c: (R)-2-(2,3-Dihydro-benzofuran-3-yl)-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylaminehydrochloride Step 1:(1S,2S,6R,8S)-4-(2,3-Dihydro-benzofuran-3-ylmethyl)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]decane

To a solution of(1S,2S,6R,8S)-4-Benzofuran-3-ylmethyl-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]decane(5.00 g; 10.72 mmol; 1.00 eq.) in methanol (100.00 ml; 20.00 V) in atiny clave was added palladium on carbon (10 wt %) (2.28 g; 2.14 mmol;0.20 eq.). The contents were hydrogenated under a H₂ pressure of 5Kg/cm² for 3 h. TLC analysis revealed complete conversion. The reactionmixture was filtered through celite and the filtrate was evaporated. Thecrude was purified by Biotage-isolera column chromatography (C18 column;mobile phase: ACN/H₂O; 50:50 isocratic) to get a(1S,2S,6R,8S)-4-(2,3-Dihydro-benzofuran-3-ylmethyl)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]decane(4.10 g; 13.13 mmol; 122.5%; pale yellow liquid; Purified Product).

GCMS: m/z: 312.3.

Step 2: (1S,2S,6R,8S)-4-[1-Chloro-2-(7-methyl-benzofuran-3-yl)-ethyl]-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]decane

Dichloromethane (2.46 ml; 38.44 mmol; 3.00 eq.) in THF (40.00 ml; 10.00V) was taken in a RB-flask under a positive pressure of nitrogen andcooled to −95° C. using liquid nitrogen-ethanol mixture. To this n-butyllithium (1.6 M in THF) (8.81 ml; 14.09 mmol; 1.10 eq.) was added dropwise through the sides of the RB-flask (at a medium rate, addition tookabout 20 min.) so that the internal temperature was maintained between−95° C. and −100° C. After addition, the reaction mixture was stirredfor 25 minutes. During the course of the reaction a white precipitatewas formed (the internal temperature was maintained between −95° C. and−100° C.). Then a solution of(1S,2S,6R,8S)-4-(2,3-Dihydro-benzofuran-3-ylmethyl)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]decane(4.00 g; 12.81 mmol; 1.00 eq.) in THF (15.00 ml; 3.75 V) was added dropwise through the sides of the RB-flask (about 25 min) so that theinternal temperature was maintained between −95° C. and −100° C. Afteraddition, immediately zinc chloride (0.5 M in THF) (25.62 ml; 12.81mmol; 1.00 eq.) was added drop wise through the sides of the RB-flask(at a medium rate, addition took about 25 min.) so that the internaltemperature was maintained between −95° C. and −100° C. The reactionmixture was then slowly allowed to attain RT and stirred at RT for 18 h.The reaction mixture was concentrated (temperature of the bath 30° C.).The residue was partitioned between diethyl ether and saturated NH₄Clsolution. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated (temperature of bath 30° C.) to afford(1S,2S,6R,8S)-4-[(S)-1-Chloro-2-(2,3-dihydro-benzofuran-3-yl)-ethyl]-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]decane(4.60 g; 12.75 mmol; 99.5%; yellow oil; Crude Product). The product wasunstable in LCMS and HPLC conditions and was confirmed by ¹H NMR.

Chiral data could not be taken for the product. The product was assumedto be major S-isomer.

1H NMR, 400 MHz, CDCl₃: 7.29 (d, J=6.72 Hz, 1H), 7.21-7.10 (m, 1H),6.90-6.77 (m, 2H), 4.68-4.65 (m, 1H), 4.32-4.29 (m, 2H), 3.65-3.60 (m,1H), 2.40-2.08 (m, 4H), 1.94-1.85 (m, 2H), 1.42 (s, 3H), 1.33 (s, 3H),1.22 (s, 3H), 1.17-1.15 (m, 1H), 0.86 (s, 3H).

Step 3:(1S,2S,6R,8S)-4-[(R)-2-(2,3-Dihydro-benzofuran-3-yl)-1-(1,1,1,3,3,3-hexamethyl-disilazan-2-yl)-ethyl]-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]decane

A solution of(1S,2S,6R,8S)-4-[(S)-1-Chloro-2-(2,3-dihydro-benzofuran-3-yl)-ethyl]-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]decane(4.60 g; 12.75 mmol; 1.00 eq.) in THF (45.00 ml; 9.78 V) under apositive pressure of nitrogen atmosphere was cooled to −78° C. To this asolution of Lithium(bistrimethylsilyl)amide (1.0 M in THF) (16.58 ml;16.58 mmol; 1.30 eq.) was added drop wise over a period of 30 minutes.The reaction mixture was allowed to attain RT and stirred at RT for 18h. The reaction mixture was evaporated at 30° C. The residue wastriturated with hexane and the solid formed was filtered. The filtratewas allowed to stand for some time under vacuum and any solid if formedwas filtered again. The filtrate was concentrated at 30° C. to get(1S,2S,6R,8S)-4-[(R)-2-(2,3-Dihydro-benzofuran-3-yl)-1-(1,1,1,3,3,3-hexamethyl-disilazan-2-yl)-ethyl]-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]decane(3.77 g; 7.76 mmol; 60.9%; yellow oil; Crude Product). The crude productwas taken to next step without purification. The product was confirmedby ¹H-NMR and was unstable in LCMS conditions.

The major product formed is the R-isomer.

1H NMR, 400 MHz, CDCl₃: 7.22-7.10 (m, 2H), 6.90-6.79 (m, 2H), 4.62-4.59(m, 1H), 4.33-4.27 (m, 1H), 2.34-2.20 (m, 2H), 2.07-2.05 (m, 1H),1.94-1.84 (m, 2H), 1.40 (s, 3H), 1.30 (s, 3H), 1.15-1.13 (m, 1H), 0.86(s, 3H), 0.10 (s, 18H).

Step 4: (R)-2-(2,3-Dihydro-benzofuran-3-yl)-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylaminehydrochloride

A stirred solution of(1S,2S,6R,8S)-4-[(R)-2-(2,3-Dihydro-benzofuran-3-yl)-1-(1,1,1,3,3,3-hexamethyl-disilazan-2-yl)-ethyl]-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]decane(3.77 g; 7.76 mmol; 1.00 eq.) in Et₂O (35.00 ml; 9.28 V) under nitrogenatmosphere was cooled to −10° C. To this 2M solution of Hydrochloricacid in diethyl ether (9.70 ml; 19.41 mmol; 2.50 eq.) was added dropwise. The reaction mixture was stirred at RT for 2 h. The reactionmixture was evaporated to dryness under reduced pressure to get a solid.The solid formed was triturated with diethyl ether, filtered, washedwith diethyl ether and dried under vacuum to get(R)-2-(2,3-Dihydro-benzofuran-3-yl)-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylaminehydrochloride (2.30 g; 5.25 mmol; 67.7%; pale brown solid; PurifiedProduct).

Analysis showed the presence of isomers (˜65.50%+20.75%) at theindicated (*) position.

LCMS: 4.73 min., 86.25% (max), 80.47% (220 nm), 342.20 (M+1).

1H NMR, 400 MHz, DMSO-d6: 8.11 (s, 3H), 7.23-7.19 (m, 1H), 7.13-7.10 (m,1H), 6.85 (t, J=7.40 Hz, 1H), 6.77 (d, J=8.04 Hz, 1H), 4.61-4.57 (m,1H), 4.48-4.45 (m, 1H), 4.25-4.22 (m, 1H), 3.68-3.62 (m, 1H), 2.90-2.85(m, 1H), 2.34-2.32 (m, 1H), 2.19-2.17 (m, 1H), 2.02-1.99 (m, 2H),1.89-1.77 (m, 3H), 1.39 (s, 3H), 1.25 (s, 3H), 1.17-1.14 (m, 1H), 0.82(s, 3H).

By similar sequences the following compounds can be prepared:

wherein the group Y denotes for example one of the following groups:

In accordance with the definitions above Rx and Ry may denoteindependently Hal, CN, R^(3a), OR^(3a), CONHR^(3a), CONR^(3b)R^(3a),CONH₂, NR^(3a)COR^(3b), SO₂R^(3a), SOR^(3a), NHR^(3a), N(R^(3a))₂,(CH₂)_(q)—SR^(3a), (CH₂)_(q)—N(R^(3a))₂ and/or (CH₂)_(q)—Z. Inparticular R may be selected from a group consisting of F, Cl, Br, OCH₃,OC₂H₅, CH₂OCH₃, CH₃, C₂H₅, CF₃, OCF₃, phenyl, biphenyl, naphthyl, furyl,thienyl, pyrrolyl, imidazolyl, morpholinyl, piperazinyl, benzofuryl,benzodioxolyl and/or pyridyl or even more preferably selected from agroup comprising F, Cl, Br, CH₃, C₂H₅, CF₃, OCH₃, OC₂H₅, COCF₃, SCH₃,SC₂H₅, N(CH₃)₂, CH₂N(CH₃)₂ and/or N(C₂H₅)₂.

Intermediate 2

Step 1: benzofuran-3-ylmethanol

A solution of 1-Benzofuran-3-carbaldehyde (5 g, 34.2 mmol) in methanol(50 mL) was cooled with ice and sodium borohydride (1.9 g, 51.3 mmol)was added portionwise. The reaction mixture was stirred at roomtemperature for 1 h. The reaction mixture was concentrated and theresidue was partitioned between saturated ammonium chloride andethylacetate. The organic layer was separated, dried over sodium sulfateand concentrated. The crude product (5.0 g, colourless liquid, 98%) wastaken as such for next step without purification.

¹H NMR (400 MHz, CDCl₃): δ 7.70-7.68 (m, 1H), 7.62 (s, 1H), 7.52-7.50(m, 1H), 7.36-7.26 (m, 2H), 4.86 (s, 2H).

Step 2: 3-(bromomethyl)benzofuran

A cold (0° C.) solution of benzofuran-3-ylmethanol (5.0 g, 33.7 mmol) indiethyl ether (50 mL) was treated with phosphorus tribromide (1.1 mL,11.2 mmol) and the reaction mixture was stirred at 0° C. for 30 min. Thereaction mixture was then poured into ice and extracted with ether. Theorganic layer was dried over sodium sulfate and concentrated. The crude(7.1 g, yellow liquid, 100%) was taken as such for next step withoutpurification.

¹H NMR (400 MHz, CDCl₃): δ 7.74-7.71 (m, 2H), 7.53 (s, 1H), 7.39-7.31(m, 2H), 4.65 (s, 2H).

Step 3:2-(benzofuran-3-ylmethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A solution of 3-(bromomethyl)benzofuran (7.1 g, 33.8 mmol) in degassed1, 4-dioxane (70 ml) was treated with bis(pinacolato)diboron (10.3 g,40.5 mmol), potassium carbonate (13.9 g, 101.0 mmol),tetrakis(triphenylphosphine) palladium(0) (1.9 g, 1.7 mmol) and themixture heated at 100° C. for 12h The contents of the flask were cooledto room temperature and filtered through a celite bed. Filtrate wasconcentrated and the crude was purified by flash column chromatographyon silica gel, eluting with 2-5% of ethylacetate in petroleum ether toget the title compound (6.1 g, 69%) as yellow oil.

¹H NMR (400 MHz, CDCl₃) b 7.57-7.52 (m, 2H), 7.46-7.44 (m, 1H),7.30-7.21 (m, 2H), 2.23 (s, 2H), 1.29 (s, 12H).

Step 4: 2-(benzofuran-3-ylmethyl)boronic acid (+)-pinanediol ester

A solution of2-(benzofuran-3-ylmethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.1g, 23.6 mmol) in diethyl ether (60 ml) was treated with (1S, 2S, 3R,5S)-(+)-pinanediol (6.0 g, 35.4 mmol). The reaction mixture was stirredat room temperature for 12 h then the mixture was washed with watertwice, then with brine and dried over anhydrous sodium sulphate, thenconcentrated. The crude product was purified by flash columnchromatography on silica gel, eluting with 5% of ethyl acetate inpetroleum ether, to afford the title compound (6.3 g, 82%).

¹H NMR (400 MHz, CDCl₃): δ 7.58-7.56 (m, 1H), 7.55-7.53 (m, 1H),7.46-7.44 (m, 1H), 7.28-7.23 (m, 2H), 4.33 (dd, J=1.88, 8.76 Hz, 1H),2.34-2.32 (m, 1H), 2.28 (s, 2H), 2.22-2.21 (m, 1H), 2.08 (t, J=5.88 Hz,1H), 1.42 (s, 3H), 1.29 (s, 3H), 1.13 (d, J=10.92 Hz, 1H), 0.85 (s, 3H).GCMS: m/z: 310.

Step 5: [(1S)-1-chloro-2-(benzofuran-3-ylmethyl)boronic acid(+)-pinanediol ester

To a cooled (−100° C.) mixture of dichloromethane (6.3 ml, 60.9 mmol)and anhydrous tetrahydrofuran (36 ml) was added n-butyl lithium (1.6 Min hexanes, 14.0 ml, (22.3 mmol) over 20 min. After stirring for 20 min.at −100° C., a solution of 2-(benzofuran-3-ylmethyl)boronic acid(+)-pinanediol ester (6.3 g, 20.3 mmol) in anhydrous THF (22 ml) wasadded over 20 min. Then a solution of zinc chloride (0.5 M in THF, 36.5mL, 18.2 mmol) was added at −100° C. over 30 min. The mixture wasallowed to reach room temperature and stirred for 18 h and concentrated.To the resulting oil was added diethyl ether and saturated ammoniumchloride. The organic layer was dried over anhydrous sodium sulphate andconcentrated in vacuo. The residue (7.3 g, 99%) was taken as such forthe next step.

¹H NMR (400 MHz, DMSO-d6): δ 7.60-7.57 (m, 2H), 7.49-7.47 (m, 1H),7.31-7.25 (m, 2H), 4.36-4.34 (m, 1H), 3.31-3.29 (m, 1H), 3.24-3.22 (m,1H), 2.35-2.31 (m, 1H), 2.14-2.12 (m, 1H), 2.06 (t, J=5.84 Hz, 1H),1.90-1.86 (m, 2H), 1.42 (s, 3H), 1.04 (d, J=11.04 Hz, 1H), 0.85 (s, 3H).GCMS: m/z: 358.2.

Step 6: [(1R)-1-[bis(trimethylsilyl)amino]-2-(benzofuran-3-ylmethyl)boronic acid (+)-pinanediol ester

To a cooled (−78° C.) solution of[(1S)-1-chloro-2-(benzofuran-3-ylmethyl)boronic acid (+)-pinanediolester (7.3 g, 20.3 mmol) in 40 ml of anhydrous tetrahydrofuran was addedlithium bis(trimethylsilyl)amide (1M in THF, 25.5 ml, 25.5 mmol). Themixture was allowed to room temperature, stirred for 18 h andconcentrated to dryness. To the resulting residue was added hexane, andthen the precipitated solid was filtered off. The filtrate wasconcentrated to give the required crude product (6.7 g, 68%) which wastaken as such for the next step without purification.

¹H NMR (400 MHz, CDCl₃): δ 7.60-7.59 (m, 1H), 7.50-7.45 (m, 2H),7.28-7.24 (m, 2H), 4.31 (dd, J=1.56, 8.70 Hz, 1H), 3.18-3.14 (m, 1H),2.92-2.90 (m, 1H), 2.75-2.72 (m, 1H), 2.34-2.30 (m, 1H), 2.15-2.14 (m,1H), 2.03 (t, J=5.68 Hz, 1H), 1.88-1.80 (m, 2H), 1.39 (s, 3H), 1.30 (s,3H), 1.01 (d, J=10.88 Hz, 1H), 0.84 (s, 3H), 0.09 (s, 18H).

Step 7: [(1R)-1-amino-2-(benzofuran-3-ylmethyl)boronic acid(+)-pinanediol ester trifluoroacetate

A cooled (0° C.) solution of[(1R)-1-[bis(trimethylsilyl)amino]-2-(benzofuran-3-ylmethyl)boronic acid(+)-pinanediol ester (6.7 g, 13.9 mmol) in diethyl ether (30 ml) wastreated with trifluoroacetic acid (3.2 ml, 41.7 mmol) dropwise. Thereaction mixture was then stirred at RT for 3 h. Precipitation was seen.The reaction mixture was cooled to 0° C. and filtered. The filteredsolid was washed with cold ether and dried under vacuum to afford thetitle compound (2.3 g, white solid, 36%).

¹H NMR (400 MHz, DMSO-d₆): δ 7.66 (s, 1H), 7.61-7.60 (m, 1H), 7.47-7.45(m, 1H), 7.29-7.20 (m, 2H), 4.30-4.28 (m, 1H), 3.27-3.16 (m, 3H),2.25-2.13 (m, 3H), 1.94 (t, J=5.56 Hz, 1H), 1.86-1.81 (m, 2H), 1.25 (s,6H), 1.01 (d, J=8.00 Hz, 1H), 0.75 (s, 3H).

Intermediate 3

Step 1: 4,4,5,5-tetramethyl-2-(4-methylbenzyl)-1,3,2-dioxaborolane

A solution of 4-methylbenzylbromide (10.0 g, 53.5 mmol) in degassed 1,4-dioxane (100 ml) was treated with bis(pinacolato)diboron (16.5 g, 64.2mmol), potassium carbonate (22.6 g, 160.5 mmol),tetrakis(triphenylphosphine) palladium(0) (3.1 g, 2.7 mmol) and themixture heated at 100° C. for 12h The contents of the flask were cooledto room temperature and filtered through a celite bed. Filtrate wasconcentrated and the residue was dissolved in ethylacetate and washedwith brine. The organic layer was dried over sodium sulfate andconcentrated. The crude product was purified by Flash columnchromatography on silica gel, eluting with 2% of ethylacetate inpetroleum ether to get the title compound (9.3 g, 70%) as colourlessliquid.

¹H NMR (400 MHz, CDCl₃) b 7.10-7.04 (m, 4H), 2.30 (s, 3H), 2.26 (s, 2H),1.24 (s, 12H).

Step 2: 2-(4-methylbenzyl)boronic acid (+)-pinanediol ester

A solution of 4,4,5,5-tetramethyl-2-(4-methylbenzyl)-1,3,2-dioxaborolane(9.3 g, 37.6 mmol) in diethyl ether (90 ml) was treated with (1S, 2S,3R, 5S)-(+)-pinanediol (9.7 g, 56.4 mmol). The reaction mixture wasstirred at room temperature for 12 h then the mixture was washed withwater twice, then with brine and dried over anhydrous sodium sulphate,then concentrated. The crude product was purified by flash columnchromatography on silica gel, eluting with 3% of ethyl acetate inpetroleum ether, to afford the title compound (11.0 g, colourlessliquid, 93%).

¹H NMR (400 MHz, CDCl₃): δ 400 MHz, CDCl3: δ 7.08 (s, 4H), 4.28 (dd,J=1.88, 8.74 Hz, 1H), 2.34-2.28 (m, 6H), 2.21-2.17 (m, 1H), 2.06 (t,J=5.80 Hz, 1H), 1.91-1.81 (m, 2H), 1.39 (s, 3H), 1.29 (s, 3H), 1.07-0.91(m, 1H), 0.84 (s, 3H). GCMS: m/z: 284.3.

Step 3: [(1S)-1-chloro-2-(4-methylbenzyl)boronic acid (+)-pinanediolester

To a cooled (−100° C.) mixture of dichloromethane (4.0 ml, 62.3 mmol)and anhydrous tetrahydrofuran (40 ml) was added n-butyl lithium (1.6 Min hexanes, 14.3 ml, (22.8 mmol) over 20 min. After stirring for 20 min.at −100° C., a solution of 2-(4-methylbenzyl)boronic acid (+)-pinanediolester (5.9 g, 20.7 mmol) in anhydrous THF (20 ml) was added over 20 min.Then a solution of zinc chloride (0.5 M in THF, 37.3 mL, 20.7 mmol) wasadded at −100° C. over 30 min. The mixture was allowed to reach roomtemperature and stirred for 18 h and concentrated. To the resulting oilwas added diethyl ether and saturated ammonium chloride. The organiclayer was dried over anhydrous sodium sulphate and concentrated invacuo. The residue (6.5 g, pale yellow oil, 94%) was taken as such forthe next step.

¹H NMR (400 MHz, CDCl₃): δ 7.18-7.08 (m, 5H), 4.37 (dd, J=1.32, 8.74 Hz,1H), 3.77-3.75 (m, 1H), 3.67-3.63 (m, 1H), 3.19-3.17 (m, 1H), 3.10-3.08(m, 1H), 2.36-2.31 (m, 5H), 2.09 (t, J=5.84 Hz, 1H), 1.93-1.86 (m, 4H),1.39 (s, 3H), 1.30 (s, 3H), 1.13-1.10 (m, 1H), 0.84 (s, 3H). GCMS: m/z:332.0.

Step 4: [(1R)-1-[bis(trimethylsilyl)amino]-2-(4-methylbenzyl)boronicacid (+)-pinanediol ester

To a cooled (−78° C.) solution of [(1S)-1-chloro-2-(4-methylbenzyl)boronic acid (+)-pinanediol ester (6.5 g, 19.5 mmol) in 40 ml ofanhydrous tetrahydrofuran was added lithium bis(trimethylsilyl)amide (1Min THF, 24.4 ml, 24.4 mmol). The mixture was allowed to attain roomtemperature, stirred for 18 h and concentrated to dryness. To theresulting residue was added hexane, and then the precipitated solid wasfiltered off. The filtrate was concentrated to give the required crudeproduct (7.5 g, brown oil, 84%) which was taken as such for the nextstep without purification.

¹H NMR (400 MHz, CDCl₃): δ 7.15-7.11 (m, 2H), 7.08-7.05 (m, 2H), 4.28(dd, J=1.88, 8.72 Hz, 1H), 3.02-2.99 (m, 1H), 2.80-2.78 (m, 1H),2.64-2.61 (m, 1H), 2.33-2.30 (m, 5H), 2.29-2.29 (m, 1H), 2.01 (t, J=5.80Hz, 1H), 2.00-1.81 (m, 2H), 1.38 (s, 3H), 1.29 (s, 3H), 0.98-0.96 (m,1H), 0.84 (s, 3H), 0.09 (s, 18H).

Step 7: [(1R)-1-amino-2-(4-methylbenzyl)boronic acid (+)-pinanediolester trifluoroacetate

A cooled (0° C.) solution of[(1R)-1-[bis(trimethylsilyl)amino]-2-(4-methylbenzyl)boronic acid(+)-pinanediol ester (7.5 g, 16.4 mmol) in diethyl ether (35 ml) wastreated with trifluoroacetic acid (3.8 ml, 49.1 mmol) dropwise. Thereaction mixture was then stirred at RT for 3 h. Precipitation was seen.The reaction mixture was cooled to 0° C. and filtered. The filteredsolid was washed with cold ether and dried under vacuum to afford thetitle compound (2.8 g, white solid, 40%).

¹H NMR (400 MHz, CDCl₃): δ 7.75 (s, 3H), 7.17-7.11 (m, 4H), 4.32-4.30(m, 1H), 3.18-3.11 (m, 2H), 3.09-2.97 (m, 1H), 2.32 (s, 3H), 2.27-2.15(m, 3H), 1.97 (t, J=5.52 Hz, 1H), 1.97-1.95 (m, 1H), 1.89-1.89 (m, 1H),1.37 (s, 3H), 1.28 (s, 3H), 1.09-1.08 (m, 1H), 0.84 (s, 3H).

Example 1:[(1R)-2-(4-fluorophenyl)-1-[3-(2-oxo-3-phenyl-imidazolidin-1-yl)propanoylamino]ethyl]boronicacid (Compound No. 14:) Step 1

To a solution of(R)-2-(4-Fluoro-phenyl)-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylaminehydrochloride (0,774 mmol; 330.00 mg) in N,N-Dimethylformamide, (max.0.003% H2O) (123,136 mmol; 10.00 ml) was added3-(2-Oxo-3-phenyl-imidazolidin-1-yl)-propionic acid (0,774 mmol; 181.42mg) at −15° C. under argon atmosphere. Then N-Ethyl-diisopropyl-amine(2,323 mmol; 0.40 ml) and TBTU (0,929 mmol; 298.40 mg) were added andthe orange solution was stirred 15 min at −10° C., then 2h at RT. Thereaction solution was cooled with ice, diluted with ethyl acetate andbrine. The organic phase was washed with 3 times with brine, dried oversodium sulfate, filtered, concentrated in vacuum and purified by flashchromatography (heptane/EtOAc 0→100%) over silica. After removal of anysolvent in vacuum the title compound was obtained as colourless oil.Yield: (280.8 mg; 68%). LCMS: 534 (M+H).

Step 2

To a two phase system ofN—[(R)-2-(4-Fluoro-phenyl)-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-3-(2-oxo-3-phenyl-imidazolidin-1-yl)-propionamide(0,509 mmol; 280.00 mg) in n-Pentane 99+% (12.00 ml) and Methanol(147,931 mmol; 6.00 ml) were added Isobutylboronic acid (2,037 mmol;207.61 mg; 4.00 aq.) and Hydrochloric acid c(HCl)=2 mol/l (2 N) (4,725mmol; 2.36 ml) at 0° C. The colorless mixture was stirred at RT overnight. The reaction mixture was washed with pentane (4×). The methanolicaq. layer was evaporated (bath temperature 30° C.), the residue wasbasified with 1N NaOH and extracted with DCM (4×). The aq. phase wasacidified with 1 N HCl and extracted again with DCM (5×). The combinedorganic layers were dried over Na₂SO₄, filtered and reduced to dryness.After lyophilisation the title compound was obtained as white fluffypowder (135.9 mg, 67%).

1H NMR (500 MHz, DMSO-d6) ppm=7.53-7.46 (m, 2H), 7.32-7.26 (m, 2H),7.17-7.11 (m, 2H), 7.01-6.93 (m, 3H), 3.72-3.65 (m, 2H), 3.40-3.30 (m,4H), 3.15-3.08 (m, 1H), 2.76 (dd, J=13.9, 5.5, 1H), 2.62 (dd, J=13.9,9.1, 1H), 2.31-2.26 (m, 2H). LCMS: 328.1 (M+H—H₂O). HPLC (Method B) Rt:4.35.

Following examples 2 to 35 were prepared using similar procedures asdescribed above.

Example 2:[(1R)-2-(3-ethylphenyl)-1-[4-(2-oxooxazolidin-3-yl)butanoylamino]-ethyl]boronicacid (Compound No. 1)

1H NMR (400 MHz, DMSO-d6) ppm=7.14-7.11 (m, 1H), 6.97-6.93 (m, 3H),4.23-4.19 (m, 2H), 3.47-3.43 (m, 2H), 3.07-2.99 (m, 2H), 2.95-2.91 (m,1H), 2.75-2.70 (m, 1H), 2.56-2.51 (m, 2H), 2.49-2.46 (m, 1H), 2.09-2.05(m, 2H), 1.66-1.59 (m, 2H), 1.11-1.07 (m, 3H). LCMS: 331.2 (M+H—H2O).HPLC (Method A) Rt: 2.69.

Example 3:[(1S)-1-[3-(2-oxopyrrolidin-1-yl)propaqanoylamino]-2-phenyl-ethyl]-boronicacid (Compound No. 2)

1H NMR (400 MHz, DMSO-d6) ppm=7.26-7.19 (m, 2H), 7.17-7.11 (m, 3H),3.33-3.27 (m, 2H), 3.25-3.17 (m, 2H), 3.08 (dd, J=9.1, 5.5, 1H), 2.77(dd, J=14.0, 5.5, 1H), 2.60 (dd, J=13.9, 9.2, 1H), 2.27-2.21 (m, 2H),2.18-2.10 (m, 2H), 1.85-1.75 (m, 2H). LCMS: 287.0 (M+H—H2O). HPLC(Method B) Rt: 2.65.

Example 4:[(1S)-1-[3-(2-oxo-1-piperidyl)propanoylamino]-2-phenyl-ethyl]boronicacid (Compound No. 3)

1H NMR (400 MHz, DMSO-d6) ppm=7.29-7.08 (m, 5H), 3.40-3.31 (m, 2H),3.17-3.11 (m, 2H), 3.09-3.02 (m, 1H), 2.81-2.72 (m, 1H), 2.65-2.56 (m,1H), 2.29-2.21 (m, 2H), 2.17-2.09 (m, 2H), 1.67-1.53 (m, 4H). LCMS:301.0 (M+H—H2O). HPLC (Method B) Rt: 3.04.

Example 5:[(1R)-1-[3-(2-oxopyrrolidin-1-yl)propanoylamino]-2-(p-tolyl)ethyl]-boronicacid (Compound No. 4)

1H NMR (400 MHz, DMSO-d6) ppm=7.02 (s, 4H), 3.29 (t, J=6.88 Hz, 2H),3.18-3.23 (m, 2H), 3.12-3.15 (m, 1H), 2.76-2.71 (m, 1H), 2.57-2.63 (m,1H), 2.18-2.22 (m, 5H), 2.11-2.15 (m, 2H), 1.79-1.84 (m, 2H). LCMS:301.2 (M+H—H2O). HPLC (Method A) Rt: 2.26.

Example 6:[(1R)-1-[3-(2,6-dioxo-1-piperidyl)propanoylamino]-2-phenyl-ethyl]-boronicacid (Compound No. 5)

1H NMR (400 MHz, DMSO-d6) ppm=7.27-7.20 (m, 2H), 7.18-7.11 (m, 3H),3.26-3.13 (m, 2H), 3.07 (dd, J=8.7, 5.7, 1H), 2.79 (dd, J=13.8, 5.7,1H), 2.64 (dd, J=13.9, 8.8, 1H), 2.26-2.15 (m, 4H), 2.06 (t, J=7.5, 2H),1.68 (p, J=7.5, 2H). LCMS: 315.2 (M+H—H2O). HPLC (Method B) Rt: 2.29.

Example 7:[(1R)-2-(2-naphthyl)-1-[3-(2-oxopyrrolidin-1-yl)propanoylamino]-ethyl]boronicacid (Compound No. 6)

1H NMR (400 MHz, DMSO-d6) ppm=7.85-7.74 (m, 3H), 7.64-7.59 (m, 1H),7.47-7.37 (m, 2H), 7.34 (dd, J=8.4, 1.7, 1H), 3.32-3.20 (m, 3H),3.20-3.07 (m, 2H), 2.95 (dd, J=14.0, 5.3, 1H), 2.79 (dd, J=13.9, 9.3,1H), 2.22 (td, J=6.9, 3.0, 2H), 2.12-2.02 (m, 2H), 1.77-1.59 (m, 2H).LCMS: 337.2 (M+H—H2O). HPLC (Method B) Rt: 3.77.

Example 8:[(1R)-2-(2-naphthyl)-1-[3-(2-oxo-1-piperidyl)propanoylamino]ethyl]-boronicacid (Compound No. 7)

1H NMR (400 MHz, DMSO-d6) ppm=7.84-7.75 (m, 3H), 7.64-7.60 (m, 1H),7.47-7.38 (m, 2H), 7.34 (dd, J=8.4, 1.7, 1H), 3.39-3.28 (m, 2H), 3.20(dd, J=9.1, 5.5, 1H), 3.12-3.01 (m, 2H), 2.95 (dd, J=14.0, 5.5, 1H),2.79 (dd, J=13.9, 9.2, 1H), 2.29-2.18 (m, 2H), 2.13-2.00 (m, 2H),1.59-1.42 (m, 4H). LCMS: 351.2 (M+H—H2O). HPLC (Method B) Rt: 3.96.

Example 9:[(1R)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-[3-(2-oxopyrrolidin-1-yl)propanoylamino]ethyl]boronicacid (Compound No. 8)

1H NMR (400 MHz, DMSO-d6) ppm=6.68-6.70 (m, 1H), 6.62-6.63 (m, 1H),6.56-6.59 (m, 1H), 4.14-4.17 (m, 4H), 3.30 (t, J=6.92 Hz, 2H), 3.19-3.25(m, 2H), 3.08-3.12 (m, 1H), 2.64-2.71 (m, 1H), 2.51-2.56 (m, 1H),2.19-2.21 (m, 2H), 2.15 (t, J=7.80 Hz, 2H), 1.84-1.86 (m, 2H). LCMS:345.2 (M+H—H2O). HPLC (Method A) Rt: 1.86.

Example 10:[(1R)-1-[3-(2-oxo-1-piperidyl)propanoylamino]-2-(p-tolyl)ethyl]boronicacid (Compound No. 9)

1H NMR (400 MHz, DMSO-d6) ppm=7.02 (s, 4H), 3.35 (t, J=7.00 Hz, 2H),3.08-3.15 (m, 3H), 2.70-2.75 (m, 1H), 2.56-2.62 (m, 1H), 2.21-2.24 (m,5H), 2.11-2.12 (m, 2H), 1.60-1.60 (m, 4H). LCMS: 315.2 (M+H—H2O). HPLC(Method A) Rt: 2.49.

Example 11:[(1R)-2-(1-naphthyl)-1-[3-(2-oxopyrrolidin-1-yl)propanoylamino]ethyl]-boronicacid (Compound No. 10)

1H NMR (400 MHz, DMSO-d6) ppm=8.14-8.09 (m, 1H), 7.94-7.89 (m, 1H), 7.78(d, 1H), 7.60-7.50 (m, 2H), 7.46-7.41 (m, 1H), 7.39-7.34 (m, 1H),3.39-3.29 (m, 3H), 3.29-3.19 (m, 3H), 3.10 (dd, J=13.9, 9.2, 1H),2.35-2.22 (m, 2H), 2.22-2.16 (m, 2H), 1.89-1.79 (m, 2H). LCMS: 337.2(M+H—H2O). HPLC (Method A) Rt: 3.67.

Example 12:[(1R)-2-(1-naphthyl)-1-[3-(2-oxo-1-piperidyl)propanoylamino]ethyl]-boronicacid (Compound No. 11)

1H NMR (400 MHz, DMSO-d6) ppm=8.13-8.09 (m, 1H), 7.94-7.89 (m, 1H),7.81-7.76 (m, 1H), 7.60-7.49 (m, 2H), 7.47-7.41 (m, 1H), 7.39-7.34 (m,1H), 3.40 (t, J=7.0, 2H), 3.33 (dd, J=13.8, 5.2, 1H), 3.24-3.05 (m, 4H),2.38-2.22 (m, 2H), 2.21-2.12 (m, 2H), 1.67-1.56 (m, 4H). LCMS: 351.2(M+H—H2O). HPLC (Method B) Rt: 3.86.

Example 13:[(1R)-1-[3-(2-oxo-4-phenyl-pyrrolidin-1-yl)propanoylamino]-2-phenyl-ethyl]boronicacid (Compound No. 12)

1H NMR (400 MHz, DMSO-d6) ppm=7.33-7.26 (m, 2H), 7.26-7.16 (m, 5H),7.16-7.05 (m, 3H), 3.69-3.58 (m, 1H), 3.50-3.34 (m, 3H), 3.30-3.22 (m,11H), 3.20-3.12 (m, 1H), 2.85-2.75 (m, 1H), 2.70-2.56 (m, 2H), 2.35-2.24(m, 3H). LCMS: 363.2 (M+H—H2O). HPLC (Method B) Rt: 4.16.

Example 14:[(1R)-1-[3-(2-oxoazepan-1-yl)propanoylamino]-2-phenyl-ethyl]boronic acid(Compound No. 13)

1H NMR (400 MHz, DMSO-d6) ppm=7.26-7.19 (m, 2H), 7.18-7.11 (m, 3H), 3.38(t, J=7.1, 2H), 3.26-3.19 (m, 2H), 3.16 (dd, J=8.8, 5.6, 1H), 2.80 (dd,J=13.8, 5.6, 1H), 2.65 (dd, J=13.8, 8.8, 1H), 2.37-2.30 (m, 2H), 2.21(t, J=7.1, 2H), 1.63-1.52 (m, 2H), 1.51-1.40 (m, 4H). LCMS: 315.2(M+H—H2O). HPLC (Method B) Rt: 3.4.

Example 15:[(1R)-1-[3-(2-oxo-3-phenyl-imidazolidin-1-yl)propanoylamino]-2-(p-tolyl)ethyl]boronicacid (Compound No. 15)

1H NMR (400 MHz, DMSO-d6) ppm=7.56-7.50 (m, 2H), 7.37-7.30 (m, 2H),7.05-6.98 (m, 5H), 3.75-3.66 (m, 2H), 3.44-3.33 (m, 4H), 3.20-3.14 (m,1H), 2.81-2.73 (m, 1H), 2.64 (dd, J=13.8, 8.8, 1H), 2.32 (t, J=6.8, 2H),2.20 (s, 3H). LCMS: 378.2 (M+H—H2O). HPLC (Method B) Rt: 4.48.

Example 16:[(1R)-2-(3,4-dimethylphenyl)-1-[3-(2-oxopyrrolidin-1-yl)propanoylamino]ethyl]boronicacid (Compound No. 16)

1H NMR (400 MHz, DMSO-d6) ppm=6.96-6.98 (m, 1H), 6.90 (s, 1H), 6.83-6.85(m, 1H), 3.30 (t, J=6.96 Hz, 2H), 3.19-3.25 (m, 2H), 3.11-3.14 (m, 1H),2.68-2.73 (m, 1H), 2.57-2.60 (m, 1H), 2.21-2.23 (m, 2H), 2.10-2.17 (m,8H), 1.79-1.84 (m, 2H). LCMS: 315.2 (M+H—H2O). HPLC (Method A) Rt: 2.59.

Example 17:[(1R)-1-[3-(3,3-dimethyl-2-oxo-pyrrolidin-1-yl)propanoylamino]-2-(p-tolyl)ethyl]boronicacid (Compound No. 17)

1H NMR (400 MHz, DMSO-d6) ppm=7.02-7.03 (m, 4H), 3.29 (t, J=6.88 Hz,2H), 3.09-3.18 (m, 3H), 2.71-2.76 (m, 1H), 2.57-2.67 (m, 1H), 2.15-2.22(m, 5H), 1.67-1.68 (m, 2H), 0.95 (s, 6H)). LCMS: 329.2 (M+H—H2O). HPLC(Method A) Rt: 2.86.

Example 18:[(1R)-1-[3-(2,2-dimethyl-5-oxo-pyrrolidin-1-yl)propanoylamino]-2-(p-tolyl)ethyl]boronicacid (Compound No. 18)

1H NMR (400 MHz, DMSO-d6) ppm=7.09-7.04 (m, 4H), 3.19 (td, J=7.3, 2.7,2H), 3.13 (dd, J=8.8, 5.7, 1H), 2.78 (dd, J=13.7, 5.6, 1H), 2.64 (dd,J=13.8, 8.8, 1H), 2.34-2.21 (m, 7H), 1.82-1.74 (m, 2H), 1.18-1.11 (m,6H). LCMS: 329.7 (M+H—H2O).

HPLC (Method A) Rt: 3.82.

Example 19:[(1R)-2-(benzofuran-3-yl)-1-[3-(2-oxopyrrolidin-1-yl)propanoylamino]-ethyl]boronicacid (Compound No. 19)

1H NMR (400 MHz, DMSO-d6) ppm=7.58-7.62 (m, 2H), 7.46-7.48 (m, 1H),7.19-7.29 (m, 2H), 3.30 (t, J=6.84 Hz, 2H), 3.13-3.22 (m, 3H), 2.81-2.86(m, 1H), 2.69-2.75 (m, 1H), 2.24 (t, J=6.88 Hz, 2H), 2.09-2.13 (m, 2H),1.74-1.79 (m, 2H). LCMS: 327.2 (M+H—H2O). HPLC (Method A) Rt: 2.39.

Example 20:[(1R)-2-[4-(methoxymethyl)phenyl]-1-[3-(2-oxopyrrolidin-1-yl)propanoylamino]ethyl]boronicacid (Compound No. 20)

1H NMR (400 MHz, DMSO-d6) ppm=7.15-7.17 (m, 2H), 7.10-7.12 (m, 2H), 4.30(s, 2H), 3.29 (t, J=6.84 Hz, 2H), 3.19-3.23 (m, 5H), 3.02-3.06 (m, 1H),2.73-2.78 (m, 1H), 2.58-2.62 (m, 1H), 2.22-2.25 (m, 2H), 2.14 (t, J=8.36Hz, 2H), 1.76-1.83 (m, 2H LCMS: 331.2 (M+H—H2O). HPLC (Method A) Rt:1.9.

Example 21:[(1R)-2-[4-(methoxymethyl)phenyl]-1-[3-(2-oxopyrrolidin-1-yl)propanoylamino]ethyl]boronicacid (Compound No. 21)

1H NMR (400 MHz, DMSO-d6) ppm=7.15-7.17 (m, 2H), 7.10-7.12 (m, 2H), 4.30(s, 2H), 3.29 (t, J=6.84 Hz, 2H), 3.19-3.23 (m, 5H), 3.02-3.06 (m, 1H),2.73-2.78 (m, 1H), 2.58-2.62 (m, 1H), 2.22-2.25 (m, 2H), 2.14 (t, J=8.36Hz, 2H), 1.76-1.83 (m, 2H LCMS: 331.2 (M+H—H2O). HPLC (Method C) Rt:3.48.

Example 22:[(1R)-1-[3-(1,1-dioxothiazinan-2-yl)propanoylamino]-2-(p-tolyl)ethyl]-boronicacid (Compound No. 22)

1H NMR (400 MHz, DMSO-d6) ppm=7.05-7.01 (m, 4H), 3.26-3.18 (m, 4H), 3.15(dd, J=8.3, 5.7, 1H), 3.01-2.96 (m, 2H), 2.75 (dd, J=13.7, 5.7, 1H),2.62 (dd, J=13.7, 8.4, 1H), 2.28 (t, J=7.1, 2H), 2.22 (s, 3H), 2.01-1.93(m, 2H), 1.52-1.44 (m, 2H). LCMS: 351.3 (M+H—H2O). HPLC (Method C) Rt:3.56.

Example 23:[(1R)-1-[3-[(4S)-2,5-dioxoimidazolidin-4-yl]propanoylamino]-2-(p-tolyl)ethyl]boronicacid (Compound No. 23)

1H NMR (400 MHz, DMSO-d6) ppm=10.63 (s, 1H), 7.85 (s, 1H), 7.08-6.95 (m,4H), 3.89-3.81 (m, 1H), 2.78-2.66 (m, 2H), 2.45 (dd, J=13.2, 8.0, 1H),2.38-2.25 (m, 2H), 2.22 (s, 3H), 1.99-1.88 (m, 1H), 1.73-1.62 (m, 1H).LCMS: 316.2 (M+H—H2O). HPLC (Method C) Rt: 2.65.

Example 24:[(1R)-2-(benzofuran-3-yl)-1-[3-(2-oxo-1-piperidyl)propanoylamino]-ethyl]boronicacid (Compound No. 24)

1H NMR (400 MHz, DMSO-d6) ppm=7.56-7.59 (m, 2H), 7.46 (d, J=7.92 Hz,1H), 7.19-7.28 (m, 2H), 3.33-3.44 (m, 2H), 3.12-3.13 (m, 2H), 2.95-2.98(m, 1H), 2.78-2.82 (m, 1H), 2.63-2.69 (m, 1H), 2.34 (t, J=6.72 Hz, 2H),2.10-2.12 (m, 2H), 1.49-1.54 (m, 4H). LCMS: 341.2 (M+H—H2O). HPLC(Method A) Rt: 2.58.

Example 25:[(1R)-2-(3,4-dimethylphenyl)-1-[3-(2-oxo-1-piperidyl)propanoylamino]-ethyl]boronicacid (Compound No. 25)

1H NMR (400 MHz, DMSO-d6) ppm=6.97 (d, J=7.68 Hz, 1H), 6.89-6.90 (m,1H), 6.83-6.85 (m, 1H), 3.33-3.41 (m, 2H), 3.12-3.14 (m, 2H), 2.85-2.90(m, 1H), 2.64-2.69 (m, 1H), 2.43-2.45 (m, 1H), 2.30 (t, J=6.80 Hz, 2H),2.09-2.10 (m, 8H), 1.56-1.57 (m, 4H). LCMS: 329.2 (M+H—H2O). HPLC(Method A) Rt: 2.78.

Example 26:[(1R)-2-(benzofuran-3-yl)-1-[3-(1,1-dioxothiazinan-2-yl)propanoylamino]ethyl]boronicacid (Compound No. 26)

1H NMR (400 MHz, DMSO-d6) ppm=7.67 (s, 1H), 7.54-7.46 (m, 2H), 7.29-7.16(m, 2H), 3.34-3.23 (m, 4H), 3.04-2.98 (m, 2H), 2.88-2.75 (m, 2H), 2.61(dd, J=14.7, 8.0, 1H), 2.49-2.44 (m, 2H), 1.98-1.89 (m, 2H), 1.48-1.39(m, 2H). LCMS: 377.3 (M+H—H2O). HPLC (Method C) Rt: 3.92.

Example 27:[(1R)-2-(benzofuran-3-yl)-1-[3-(2,2-dimethyl-5-oxo-pyrrolidin-1-yl)propanoylamino]ethyl]boronicacid (Compound No. 27)

1H NMR (400 MHz, DMSO-d6) ppm=7.60-7.56 (m, 2H), 7.47-7.45 (m, 1H),7.28-7.19 (m, 2H), 3.17-3.12 (m, 2H), 3.06-3.02 (m, 1H), 2.84-2.79 (m,1H), 2.73-2.67 (m, 1H), 2.30 (t, J=7.60 Hz, 2H), 2.19 (t, J=8.28 Hz,2H), 1.76-1.65 (m, 2H), 1.07 (d, J=7.04 Hz, 6H. LCMS: 355.2 (M+H—H2O).HPLC (Method A) Rt: 2.87.

Example 28:[(1R)-2-(benzofuran-3-yl)-1-[3-(3-oxomorpholin-4-yl)propanoylamino]-ethyl]boronicacid (Compound No. 28)

LCMS: 343.2 (M+H—H2O).

Example 29:[(1R)-2-(benzofuran-3-yl)-1-[3-(2-oxo-5-phenyl-oxazolidin-3-yl)propanoylamino]ethyl]boronicacid (Compound No. 29)

1H NMR (400 MHz, DMSO-d6) ppm=7.56-7.55 (m, 2H), 7.44 (d, J=7.96 Hz,1H), 7.35-7.32 (m, 3H), 7.28-7.18 (m, 4H), 5.34 (s, 1H), 3.86-3.77 (m,1H), 3.38-3.35 (m, 3H), 3.07-3.04 (m, 1H), 2.85-2.78 (m, 1H), 2.70-2.62(m, 1H), 2.37-2.32 (m, 2H). LCMS: 405.2 (M+H—H2O). HPLC (Method A) Rt:3.45.

Example 30:[(1R)-2-(benzofuran-3-yl)-1-[3-(2-oxo-1,3-oxazinan-3-yl)propanoylamino]ethyl]boronicacid (Compound No. 30)

1H NMR (400 MHz, DMSO-d6) ppm=7.58-7.56 (m, 2H), 7.45 (d, J=7.96 Hz,1H), 7.27-7.19 (m, 2H), 4.04 (m, 2H), 3.48 (m, 1H), 3.39-3.31 (m, 2H),3.18-3.16 (m, 1H), 2.97-2.93 (m, 1H), 2.81-2.76 (m, 1H), 2.68-2.62 (m,1H), 2.39-2.32 (m, 2H), 1.79-1.77 (m, 2H).

LCMS: 343.2 (M+H—H2O). HPLC (Method A) Rt: 2.33.

Example 31:[(1R)-2-(2,4-dimethylphenyl)-1-[3-(2-oxo-1-piperidyl)propanoylamino]-ethyl]boronicacid (Compound No. 31)

1H NMR (400 MHz, DMSO-d6) ppm=6.84-6.99 (m, 3H), 3.35-3.48 (m, 2H),3.14-3.21 (m, 2H), 2.89-2.92 (m, 1H), 2.65-2.70 (m, 1H), 2.54-2.57 (m,1H), 2.27-2.30 (m, 2H), 2.12-2.18 (m, 8H), 1.58-1.63 (m, 4H). LCMS:329.2 (M+H—H2O). HPLC (Method A) Rt: 2.73.

Example 32:[(1R)-2-(2,4-dimethylphenyl)-1-[3-(1,1-dioxothiazinan-2-yl)propanoylamino]ethyl]boronicacid (Compound No. 32)

1H NMR (400 MHz, DMSO-d6) ppm=6.94 (d, J=7.7, 1H), 6.90-6.86 (m, 1H),6.86-6.82 (m, 1H), 3.23-3.15 (m, 4H), 3.01-2.91 (m, 3H), 2.70 (dd,J=14.3, 5.9, 1H), 2.56 (dd, J=14.2, 9.3, 1H), 2.34-2.27 (m, 2H), 2.15(s, 6H), 2.00-1.91 (m, 2H), 1.51-1.42 (m, 2H). LCMS: 365.3 (M+H—H2O).HPLC (Method C) Rt: 4.07.

Example 33:[(1R)-2-(benzofuran-3-yl)-1-[[2-(2,4-dioxothiazolidin-3-yl)acetyl]-amino]ethyl]boronicacid (Compound No. 33)

1H NMR (400 MHz, DMSO-d6) ppm=7.67-7.62 (m, 2H), 7.55-7.50 (m, 1H),7.36-7.24 (m, 2H), 4.21-4.17 (m, 2H), 4.16-4.12 (m, 2H), 3.35 (dd,J=7.9, 5.6, 1H), 2.94 (dd, J=14.9, 5.5, 1H), 2.83 (dd, J=14.9, 7.9, 1H).LCMS: 345.2 (M+H—H2O). HPLC (Method C) Rt: 4.13.

Example 34:[(1R)-2-(benzofuran-3-yl)-1-[3-(4-ethyl-2,3-dioxo-piperazin-1-yl)propanoylamino]ethyl]boronicacid (Compound No. 34)

1H NMR (400 MHz, DMSO-d6) ppm=7.56-7.55 (m, 2H), 7.44 (d, J=7.96 Hz,1H), 7.35-7.32 (m, 3H), 7.28-7.18 (m, 4H), 5.34 (s, 1H), 3.86-3.77 (m,1H), 3.38-3.35 (m, 3H), 3.07-3.04 (m, 1H), 2.85-2.78 (m, 1H), 2.70-2.62(m, 1H), 2.37-2.32 (m, 2H). LCMS: 405.2 (M+H—H2O). HPLC (Method A) Rt:3.45.

Example 35:[(1R)-2-(benzofuran-3-yl)-1-[3-(4-methyl-2-oxo-piperazin-1-yl)propanoylamino]ethyl]boronicacid (Compound No. 35)

LCMS: 356.2 (M+H—H2O).

Example 36:[(1R)-2-(2,4-dimethylphenyl)-1-[(5-oxo-1-phenyl-pyrrolidine-2-carbonyl)amino]-ethyl]boronicacid (Compound No. 36)

1H NMR (400 MHz, DMSO-d6) ppm=7.40-7.34 (m, 1H), 7.33-7.26 (m, 2H),7.26-7.20 (m, 1H), 7.17-7.07 (m, 1H), 6.89-6.74 (m, 3H), 4.62-4.55 (m,1H), 3.24-3.17 (m, 1H), 2.75-2.67 (m, 1H), 2.62-2.51 (m, 1H), 2.50-2.20(m, 3H), 2.19-2.15 (m, 3H), 2.13 (s, 3H), 1.92-1.63 (m, 1H). MS (ESI+):363.0 [M+H—H₂O]. HPLC XBridge C8 HPLC (A19/533—LaChrom-Elite,-70173815);5 min 4 ml/min, 215 nm, buffer A 0.05% TFA/H2O, buffer B 0.04% TFA/ACN,0.0-0.2 min 5% buffer B; 0.2-0.5 min 5%-100% buffer B; 5.0-5.5 min99%-5% buffer B; Rt: 2.44 min.

Example 37:[(1R)-2-(benzofuran-3-yl)-1-[(1-phenylpyrrolidine-2-carbonyl)amino]ethyl]boronicacid (Compound No. 37)

1H NMR (400 MHz, DMSO-d6/D20) ? 5.77-5.66, 5.66-5.56, 5.49-5.31 (3x m,5H), 5.29-5.18 (m, 2H), 4.80 (t, J=7.4 Hz, 1H), 4.65-4.47 (m, 2H),2.06-1.94 (m, 1H), 1.71-1.61, 1.43-1.33 (2x m, 1H, ratio 2:1, mixture ofdiastereomers), 1.61-1.52 (m, 1H), 1.31-1.15 (m, 1H), 1.13-0.86 (m, 2H),0.36-0.19 (m, 1H), 0.14-−0.27 (m, 3H). MS (ESI+): 379.0 [M+H—H₂O]. HPLCXBridge C8 HPLC (A19/533—LaChrom-Elite,-70173815); 5 min 4 ml/min, 215nm, buffer A 0.05% TFA/H2O, buffer B 0.04% TFA/ACN, 0.0-0.2 min 5%buffer B; 0.2-0.5 min 5%-100% buffer B; 5.0-5.5 min 99%-5% buffer B; Rt:5.22 min.

Example 38:[(1R)-1-[3-(2,2-dimethyl-5-oxo-pyrrolidin-1-yl)propanoylamino]-2-(7-methylbenzofuran-3-yl)ethyl]boronicacid (Compound No. 38)

1H NMR (500 MHz, DMSO-d6+D20) d 7.63 (s, 1H), 7.40 (d, J=7.4 Hz, 1H),7.12 (t, J=7.4 Hz, 1H), 7.08 (d, J=7.1 Hz, 1H), 3.20-3.11 (m, 3H), 2.84(dd, J=15.0, 5.2 Hz, 1H), 2.73 (dd, J=15.0, 8.6 Hz, 1H), 2.41 (s, 3H),2.29 (t, J=7.5 Hz, 2H), 2.23-2.18 (m, 2H), 1.78-1.67 (m, 2H), 1.10 (s,3H), 1.09 (s, 3H). MS (ESI+): 369,2 [M+H—H₂O]. HPLC XBridge C8 HPLC(A19/533—LaChrom-Elite,-70173815); 5 min 4 ml/min, 215 nm, buffer A0.05% TFA/H2O, buffer B 0.04% TFA/ACN, 0.0-0.2 min 5% buffer B; 0.2-0.5min 5%-100% buffer B; 5.0-5.5 min 99%-5% buffer B; Rt: 3.73 min.

Example 39:[(1R)-2-[(3S)-2,3-dihydrobenzofuran-3-yl]-1-[3-(2-oxopyrrolidin-1-yl)propanoylamino]ethyl]boronicacid (Compound No. 39)

1H NMR (500 MHz, DMSO-d6/D20) d 7.15 (d, J=7.3 Hz, 1H), 7.09-7.04 (m,1H), 6.84-6.79 (m, 1H), 6.71 (d, J=8.0 Hz, 1H), 4.51 (t, J=8.9 Hz, 1H),4.17 (dd, J=9.0, 6.6 Hz, 1H), 3.43-3.29 (m, 5H), 2.98 (dd, J=10.8, 4.4Hz, 1H), 2.37-2.27 (m, 2H), 2.17-2.11 (m, 2H), 1.88-1.78 (m, 3H),1.59-1.52 (m, 1H). MS (ESI+): 329,2 [M+H—H₂O]. HPLC XBridge C8 HPLC(A19/533—LaChrom-Elite,-70173815); 5 min 4 ml/min, 215 nm, buffer A0.05% TFA/H2O, buffer B 0.04% TFA/ACN, 0.0-0.2 min 5% buffer B; 0.2-0.5min 5%-100% buffer B; 5.0-5.5 min 99%-5% buffer B; Rt: 3.27 min.

Example 40:[(1R)-2-[(3S)-7-methyl-2,3-dihydrobenzofuran-3-yl]-1-[3-(2-oxo-1-piperidyl)propanoylamino]ethyl]boronicacid (Compound No. 40)

1H NMR (500 MHz, DMSO-d6/D20) d 6.96 (d, J=7.3 Hz, 1H), 6.89 (d, J=7.4Hz, 1H), 6.72 (t, J=7.4 Hz, 1H), 4.51 (t, J=8.9 Hz, 1H), 4.16 (dd,J=9.0, 6.7 Hz, 1H), 3.44 (t, J=7.0 Hz, 2H), 3.40-3.33 (m, 1H), 3.23 (t,J=5.8 Hz, 2H), 2.90 (dd, J=10.4, 4.5 Hz, 1H), 2.35 (t, J=6.9 Hz, 2H),2.15 (t, J=6.4 Hz, 2H), 2.07 (s, 3H), 1.84-1.77 (m, 1H), 1.68-1.57 (m,4H), 1.57-1.50 (m, 1H). MS (ESI+): 357,2 [M+H—H₂O]. HPLC XBridge C8 HPLC(A19/533—LaChrom-Elite,-70173815); 5 min 4 ml/min, 215 nm, buffer A0.05% TFA/H2O, buffer B 0.04% TFA/ACN, 0.0-0.2 min 5% buffer B; 0.2-0.5min 5%-100% buffer B; 5.0-5.5 min 99%-5% buffer B; Rt: 3.23 min.

Example 41: Biological Activity

Determination of LMP7 Activity:

Measurement of LMP7 inhibition is performed in 384 well format based onfluorescence intensity assay.

Purified human immunoproteasome (0.25 nM) and serial diluted compoundsin DMSO (range of concentrations from 30 μM to 15 pM) or controls areincubated for 20 minutes or 120 minutes (long incubation) at 25° C. inassay buffer containing 50 mM Tris pH 7.4, 0.03% SDS, 1 mM EDTA and 1%DMSO. The reaction is initiated by the addition of the fluorogenicpeptide substrate, Suc-LLVY-AMC (Bachem 1-1395), at a concentration of40 μM. After 60 minutes of incubation at 37° C., fluorescence intensityis measured at λ_(ex)=350 nm and λ_(em)=450 nm with a fluorescencereader (Perkin Elmer Envision reader or equivalent).

The LMP7 activity of the compounds is summarized in Table 1. Unlessindicated otherwise the results are obtained after incubation for 20minutes.

Determination of Beta5 Activity:

Measurement of Beta5 inhibition is performed in 384 well format based onfluorescence intensity assay.

Purified human constitutive proteasome (1.25 nM) and serial dilutedcompounds in DMSO (range of concentrations from 30 μM to 15 μM) orcontrols are incubated for 20 minutes or 120 minutes (long incubation)at 25° C. in assay buffer containing 50 mM Tris pH 7.4, 0.03% SDS, 1 mMEDTA and 1% DMSO. The reaction is initiated by the addition of thefluorogenic peptide substrate, Suc-LLVY-AMC (Bachem 1-1395), at aconcentration of 40 μM. After 60 minutes of incubation at 37° C.,fluorescence intensity is measured at λ_(ex)=350 nm and λ_(em)=450 nmwith a fluorescence reader (Perkin Elmer Envision reader or equivalent).

Table 2 shows exemplarily the Beta5 activity of the some compoundsaccording to the invention and their selectivity to LMP7 versus Beta5.Unless indicated otherwise the results are obtained after incubation for20 minutes.

TABLE 1 Compound LMP7 IC50 No. Name (M) 1[(1R)-2-(3-ethylphenyl)-1-[4-(2-oxooxazolidin-3- ***yl)butanoylamino]ethyl]boronic acid 2[(1S)-1-[3-(2-oxopyrrolidin-1-yl)propanoylamino]-2- ****phenyl-ethyl]boronic acid 3[(1S)-1-[3-(2-oxo-1-piperidyl)propanoylamino]-2- ***phenyl-ethyl]boronic acid 4[(1R)-1-[3-(2-oxopyrrolidin-1-yl)propanoylamino]-2- ****(p-tolyl)ethyl]boronic acid 5[(1R)-1-[3-(2,6-dioxo-1-piperidyl)propanoylamino]- **2-phenyl-ethyl]boronic acid 6[(1R)-2-(2-naphthyl)-1-[3-(2-oxopyrrolidin-1- ****yl)propanoylamino]ethyl]boronic acid 7[(1R)-2-(2-naphthyl)-1-[3-(2-oxo-1- ****piperidyl)propanoylamino]ethyl]boronic acid 8[(1R)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-[3-(2- ****oxopyrrolidin-1-yl)propanoylamino]ethyl]boronic acid 9[(1R)-1-[3-(2-oxo-1-piperidyl)propanoylamino]-2-(p- ****tolyl)ethyl]boronic acid 10[(1R)-2-(1-naphthyl)-1-[3-(2-oxopyrrolidin-1- ***yl)propanoylamino]ethyl]boronic acid 11[(1R)-2-(1-naphthyl)-1-[3-(2-oxo-1- ***piperidyl)propanoylamino]ethyl]boronic acid 12[(1R)-1-[3-(2-oxo-4-phenyl-pyrrolidin-1- ****yl)propanoylamino]-2-phenyl-ethyl]boronic acid 13[(1R)-1-[3-(2-oxoazepan-1-yl)propanoylamino]-2- *** phenyl-ethyl]boronicacid 14 [(1R)-2-(4-fluorophenyl)-1-[3-(2-oxo-3-phenyl- ****imidazolidin-1-yl)propanoylamino]ethyl]boronic acid 15[(1R)-1-[3-(2-oxo-3-phenyl-imidazolidin-1- ****yl)propanoylamino]-2-(p-tolyl)ethyl]boronic acid 16[(1R)-2-(3,4-dimethylphenyl)-1-[3-(2-oxopyrrolidin- ****1-yl)propanoylamino]ethyl]boronic acid 17[(1R)-1-[3-(3,3-dimethyl-2-oxo-pyrrolidin-1- ****yl)propanoylamino]-2-(p-tolyl)ethyl]boronic acid 18[(1R)-1-[3-(2,2-dimethyl-5-oxo-pyrrolidin-1- ***yl)propanoylamino]-2-(p-tolyl)ethyl]boronic acid 19[(1R)-2-(benzofuran-3-yl)-1-[3-(2-oxopyrrolidin-1- ****yl)propanoylamino]ethyl]boronic acid 20[(1R)-2-[4-(methoxymethyl)phenyl]-1-[3-(2- ***oxopyrrolidin-1-yl)propanoylamino]ethyl]boronic acid 21[(1R)-1-[[2-(2-oxopyrrolidin-1-yl)acetyl]amino]-2-(p- ***tolyl)ethyl]boronic acid 22 [(1R)-1-[3-(1,1-dioxothiazinan-2- ****yl)propanoylamino]-2-(p-tolyl)ethyl]boronic acid 23[(1R)-1-[3-[(4S)-2,5-dioxoimidazolidin-4- ****yl]propanoylamino]-2-(p-tolyl)ethyl]boronic acid 24[(1R)-2-(benzofuran-3-yl)-1-[3-(2-oxo-1- ****piperidyl)propanoylamino]ethyl]boronic acid 25[(1R)-2-(3,4-dimethylphenyl)-1-[3-(2-oxo-1- ****piperidyl)propanoylamino]ethyl]boronic acid 26[(1R)-2-(benzofuran-3-yl)-1-[3-(1,1-dioxothiazinan- ****2-yl)propanoylamino]ethyl]boronic acid 27[(1R)-2-(benzofuran-3-yl)-1-[3-(2,2-dimethyl-5-oxo- ****pyrrolidin-1-yl)propanoylamino]ethyl]boronic acid 28[(1R)-2-(benzofuran-3-yl)-1-[3-(3-oxomorpholin-4- ****yl)propanoylamino]ethyl]boronic acid 29[(1R)-2-(benzofuran-3-yl)-1-[3-(2-oxo-5-phenyl- ****oxazolidin-3-yl)propanoylamino]ethyl]boronic acid 30[(1R)-2-(benzofuran-3-yl)-1-[3-(2-oxo-1,3-oxazinan- ****3-yl)propanoylamino]ethyl]boronic acid 31[(1R)-2-(2,4-dimethylphenyl)-1-[3-(2-oxo-1- ****piperidyl)propanoylamino]ethyl]boronic acid 32[(1R)-2-(2,4-dimethylphenyl)-1-[3-(1,1- ****dioxothiazinan-2-yl)propanoylamino]ethyl]boronic acid 33[(1R)-2-(benzofuran-3-yl)-1-[[2-(2,4- ****dioxothiazolidin-3-yl)acetyl]amino]ethyl]boronic acid 34[(1R)-2-(benzofuran-3-yl)-1-[3-(4-ethyl-2,3-dioxo- ****piperazin-1-yl)propanoylamino]ethyl]boronic acid 35[(1R)-2-(benzofuran-3-yl)-1-[3-(4-methyl-2-oxo- ****piperazin-1-yl)propanoylamino]ethyl]boronic acid 36[(1R)-2-(2,4-dimethylphenyl)-1-[(5-oxo-1-phenyl- ***pyrrolidine-2-carbonyl)amino]ethyl]boronic acid 37[(1R)-2-(benzofuran-3-yl)-1-[(1-phenylpyrrolidine-2- ****carbonyl)amino]ethyl]boronic acid 38[(1R)-1-[3-(2,2-dimethyl-5-oxo-pyrrolidin-1- ****yl)propanoylamino]-2-(7-methylbenzofuran-3- (long yl)ethyl]boronic acidincubation) 39 [(1R)-2-[(3S)-2,3-dihydrobenzofuran-3-yl]-1-[3-(2- ****oxopyrrolidin-1-yl)propanoylamino]ethyl]boronic acid (long incubation)40 [(1R)-2-[(3S)-7-methyl-2,3-dihydrobenzofuran-3-yl]- ****1-[3-(2-oxo-1-piperidyl)propanoylamino]ethyl]boronic acid (longincubation) * IC₅₀ > 5 μM, ** 0.5 μM < IC₅₀ < 5 μM, *** 0.05 μM < IC₅₀ <0.5 μM, **** IC₅₀ < 0.05 μM; in accordance with the method describedabove, “long incubation” means that the sample is incubated for 120 min.

TABLE 2 Selectivity Compound Beta5 IC50 LMP7 vs No. Name (M) Beta5 1[(1R)-2-(3-ethylphenyl)-1-[4-(2-oxooxazolidin-3- * ++yl)butanoylamino]ethyl]boronic acid 2[(1S)-1-[3-(2-oxopyrrolidin-1-yl)propanoylamino]- ** +++2-phenyl-ethyl]boronic acid 3[(1S)-1-[3-(2-oxo-1-piperidyl)propanoylamino]-2- ** +++phenyl-ethyl]boronic acid 4[(1R)-1-[3-(2-oxopyrrolidin-1-yl)propanoylamino]- *** ++2-(p-tolyl)ethyl]boronic acid 5[(1R)-1-[3-(2,6-dioxo-1-piperidyl)propanoylamino]- * +++2-phenyl-ethyl]boronic acid 6[(1R)-2-(2-naphthyl)-1-[3-(2-oxopyrrolidin-1- *** ++yl)propanoylamino]ethyl]boronic acid 7[(1R)-2-(2-naphthyl)-1-[3-(2-oxo-1- *** ++piperidyl)propanoylamino]ethyl]boronic acid 8[(1R)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-[3-(2- ** +++oxopyrrolidin-1-yl)propanoylamino]ethyl]boronic acid 9[(1R)-1-[3-(2-oxo-1-piperidyl)propanoylamino]-2- ** ++(p-tolyl)ethyl]boronic acid 10[(1R)-2-(1-naphthyl)-1-[3-(2-oxopyrrolidin-1- ** ++yl)propanoylamino]ethyl]boronic acid 11[(1R)-2-(1-naphthyl)-1-[3-(2-oxo-1- ** +++piperidyl)propanoylamino]ethyl]boronic acid 12[(1R)-1-[3-(2-oxo-4-phenyl-pyrrolidin-1- *** ++yl)propanoylamino]-2-phenyl-ethyl]boronic acid 13[(1R)-1-[3-(2-oxoazepan-1-yl)propanoylamino]-2- ** ++phenyl-ethyl]boronic acid 14[(1R)-2-(4-fluorophenyl)-1-[3-(2-oxo-3-phenyl- *** ++imidazolidin-1-yl)propanoylamino]ethyl]boronic acid 15[(1R)-1-[3-(2-oxo-3-phenyl-imidazolidin-1- *** ++yl)propanoylamino]-2-(p-tolyl)ethyl]boronic acid 16[(1R)-2-(3,4-dimethylphenyl)-1-[3-(2-oxopyrrolidin- ** +++++1-yl)propanoylamino]ethyl]boronic acid 17[(1R)-1-[3-(3,3-dimethyl-2-oxo-pyrrolidin-1- *** ++yl)propanoylamino]-2-(p-tolyl)ethyl]boronic acid 18[(1R)-1-[3-(2,2-dimethyl-5-oxo-pyrrolidin-1- ** +++yl)propanoylamino]-2-(p-tolyl)ethyl]boronic acid 19[(1R)-2-(benzofuran-3-yl)-1-[3-(2-oxopyrrolidin-1- *** ++++yl)propanoylamino]ethyl]boronic acid 20[(1R)-2-[4-(methoxymethyl)phenyl]-1-[3-(2- ** ++oxopyrrolidin-1-yl)propanoylamino]ethyl]boronic acid 21[(1R)-1-[[2-(2-oxopyrrolidin-1-yl)acetyl]amino]-2- ** ++(p-tolyl)ethyl]boronic acid 22 [(1R)-1-[3-(1,1-dioxothiazinan-2- *** ++yl)propanoylamino]-2-(p-tolyl)ethyl]boronic acid 23[(1R)-1-[3-[(4S)-2,5-dioxoimidazolidin-4- ** ++yl]propanoylamino]-2-(p-tolyl)ethyl]boronic acid 24[(1R)-2-(benzofuran-3-yl)-1-[3-(2-oxo-1- *** +++piperidyl)propanoylamino]ethyl]boronic acid 25[(1R)-2-(3,4-dinnethylphenyl)-1-[3-(2-oxo-1- ** +++++piperidyl)propanoylamino]ethyl]boronic acid 26[(1R)-2-(benzofuran-3-yl)-1-[3-(1,1-dioxothiazinan- *** +++2-yl)propanoylamino]ethyl]boronic acid 27[(1R)-2-(benzofuran-3-yl)-1-[3-(2,2-dimethyl-5- ** +++++oxo-pyrrolidin-1-yl)propanoylamino]ethyl]boronic acid 28[(1R)-2-(benzofuran-3-yl)-1-[3-(3-oxomorpholin-4- *** ++yl)propanoylamino]ethyl]boronic acid 29[(1R)-2-(benzofuran-3-yl)-1-[3-(2-oxo-5-phenyl- **** ++oxazolidin-3-yl)propanoylamino]ethyl]boronic acid 30[(1R)-2-(benzofuran-3-yl)-1-[3-(2-oxo-1,3- *** +++oxazinan-3-yl)propanoylamino]ethyl]boronic acid 31[(1R)-2-(2,4-dimethylphenyl)-1-[3-(2-oxo-1- ** +++++piperidyl)propanoylamino]ethyl]boronic acid 32[(1R)-2-(2,4-dimethylphenyl)-1-[3-(1,1-dioxothiazinan- ** +++2-yl)propanoylamino]ethyl]boronic acid 33[(1R)-2-(benzofuran-3-yl)-1-[[2-(2,4-dioxothiazolidin- *** ++3-yl)acetyl]amino]ethyl]boronic acid 34[(1R)-2-(benzofuran-3-yl)-1-[3-(4-ethyl-2,3-dioxo- *** ++piperazin-1-yl)propanoylamino]ethyl]boronic acid 35[(1R)-2-(benzofuran-3-yl)-1-[3-(4-methyl-2-oxo- *** ++piperazin-1-yl)propanoylamino]ethyl]boronic acid 36[(1R)-2-(2,4-dimethylphenyl)-1-[(5-oxo-1-phenyl- ** +++pyrrolidine-2-carbonyl)amino]ethyl]boronic acid 37[(1R)-2-(benzofuran-3-yl)-1-[(1-phenylpyrrolidine- ** +++++2-carbonyl)amino]ethyl]boronic acid 38[(1R)-1-[3-(2,2-dimethyl-5-oxo-pyrrolidin-1- ** +++++yl)propanoylamino]-2-(7-methylbenzofuran-3- (long (long yl)ethyl]boronicacid incubation) incubation) 39[(1R)-2-[(3S)-2,3-dihydrobenzofuran-3-yl]-1-[3-(2- ** +++++oxopyrrolidin-1-yl)propanoylamino]ethyl]boronic (long (long acidincubation) incubation) 40[(1R)-2-[(3S)-7-methyl-2,3-dihydrobenzofuran-3- * +++++yl]-1-[3-(2-oxo-1-piperidyl)propanoyl- (long (long amino]ethyl]boronicacid incubation) incubation) * IC₅₀ > 5 μM, ** 0.5 μM < IC₅₀ < 5 μM, ***0.05 μM < IC₅₀ < 0.5 μM, **** IC₅₀ < 0.05 μM, +: Selectivity < 10, ++:10 ≤ Selectivity < 30, +++: 30 ≤ Selectivity < 50, ++++: 50 ≤Selectivity < 70, +++++: Selectivity ≥ 70, n.d: not determined; inaccordance with the method described above, “long incubation” means thatthe sample is incubated for 120 min.

The following examples relate to medicaments:

Example A: Injection Vials

A solution of 100 g of an active ingredient of formula (I) and 5 g ofdisodium hydrogen phosphate in 3 l of bidistilled water is adjusted topH 6.5 using 2 N hydrochloric acid, sterile filtered, transferred intoinjection vials, lyophilised under sterile conditions and sealed understerile conditions. Each injection vial contains 5 mg of activeingredient.

Example B: Suppositories

A mixture of 20 g of an active ingredient of formula (I) with 100 g ofsoya lecithin and 1400 g of cocoa butter is melted, poured into moldsand allowed to cool. Each suppository contains 20 mg of activeingredient.

Example C: Solution

A solution is prepared from 1 g of an active ingredient of formula (I),9.38 g of NaH₂PO₄ 2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

Example D: Ointment

500 mg of an active ingredient of formula (I) are mixed with 99.5 g ofVaseline under aseptic conditions.

Example E: Tablets

A mixture of 1 kg of an active ingredient of formula (I), 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed in a conventional manner to give tablets in such away that each tablet contains 10 mg of active ingredient.

Example F: Dragees

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

Example G: Capsules

2 kg of an active ingredient of formula (I) are introduced into hardgelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active ingredient.

Example H: Ampoules

A solution of 1 kg of an active ingredient of formula (I) in 60 l ofbidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

The invention claimed is:
 1. A compound of formula (I)

wherein: LX denotes unsubstituted (CH₂)_(n); LY denotes unsubstituted(CH₂)_(m); X denotes 2-oxooxazolidinyl, 2-oxopyrrolidinyl,2-oxopiperidyl, 3-oxomorpholinyl, 2-oxoazepanyl, 2-oxoimidazolidinyl,2,5-dioxoimidazolidinyl, 2-oxooxazinanyl, 1,1-oxo-1,2-thiazinanyl,thiazolidinoyl, isothiazolodinoyl, 2,4-dioxothiazolidinyl,2-oxopiperazyl, 2,3-dioxopiperazyl, 2,6-dioxopiperidinyl,2,6-dioxopyrrolidinyl or 2,4-dioxo-1,3-thiazolidinyl, each independentlyfrom each other, unsubstituted or mono, di- or trisubstituted by A1,Ar1, COA1 and/or COAr1; Y denotes Cyc; R¹, R² denote each, independentlyfrom one another, H or C1-C4-alkyl, or R¹ and R² form together a residueof formula (CE):

R^(3a) and R^(3b) denote each, independently from one another, linear orbranched C1-C3-alkyl, wherein 1 to 5H atoms may be replaced by F, Cl, OHand/or OAlk; R4^(a) and R^(4b) denote each, independently from oneanother, H or R^(3a); A1 denotes a linear or branched C1-C6-alkyl; Alkdenotes linear or branched C1-C6-alkyl; Ar1 denotes phenyl, which isunsubstituted, mono-, bi- or trisubstituted by Hal, NO₂, CN, R^(3a),OR^(3a) NH₂, NHR^(3a) or N(R^(3a))₂; Cyc 2,4-, 3,4-, or2,3,4-substituted phenyl or unsubstituted or mono- or disubstituted 1-or 2-naphthyl, wherein the substituents are each, independently from oneanother, selected from the group consisting of Hal, CN, R^(3a) orOR^(3a); or Cyc is a residue according to formula (Fa7) or (Fb7)

wherein: G^(a) denotes, F, Cl, Br, CN, R^(3a) or OR^(3a); G^(b) denotesH, F, Cl, Br, CN, R^(3a) or OR^(3a); K^(a) and K^(b) denote each,independently from one another, H, F, Cl, Br, CN, R^(3a) or OR^(3a); ndenotes 2 or 3; m denotes 1; Hal denotes F, Cl, Br or I; and tautomers,stereoisomers or physiologically acceptable salts thereof, includingmixtures thereof in all ratios.
 2. The compound according to claim 1,wherein: R¹, R² denote, independently from one another, H orC1-C4-alkyl, or R¹ and R² form together a residue according to formula(CE)

and X denotes 2-oxopyrrolidinyl, 2-oxopiperidyl, or 2-oxoazepanyl, eachindependently from each other mono, di- or trisubstituted by A1 or Ar1;n denotes 2 or 3; and m denotes 1; and tautomers, stereoisomers orphysiologically acceptable salts thereof, including mixtures thereof inall ratios.
 3. The compound according to claim 1, wherein: R¹, R² denoteeach, independently from one another H or C1-C4-alkyl or R¹ and R² formtogether a residue according to formula (CE); and R^(3a) and R^(3b)denote each, independently from one another, linear or branchedC1-C3-alkyl, wherein 1 to 5H atoms may be replaced by F, Cl, OH and/orOAlk; Alk denotes methyl or ethyl; X denotes 2-oxopyrrolidinyl,2-oxopiperidyl, or 2-oxoazepanyl, each independently from each othermono, di- or trisubstituted by A1 or Ar1; Cyc denotes phenyl, which isunsubstituted, mono-, di- or trisubstituted by Hal, CN, R^(3a) orOR^(3a); wherein in case of monosubstitution substituents are in 3- or4-position, and wherein in case of disubstitution substituents are in2,4- or 3,4-position and in case of trisubstitution substituents are in2,3,4-position; or 1- or 2-naphthyl, each independently from oneanother, unsubstituted, mono- or disubstituted by Hal, CN, R^(3a) orOR^(3a); n denotes 2 or 3; m denotes 1; and tautomers, stereoisomers orphysiologically acceptable salts thereof, including mixtures thereof inall ratios.
 4. The compound according to claim 1, wherein: LX denotes—CH₂—CH₂— or —CH₂—CH₂—CH₂; LY denotes —CH₂—; Y denotes Cyc; R¹, R²denote each, independently from one another methyl or ethyl or R¹ and R²form together a residue according to formula (CE) as described above;and R^(3a) and R^(3b) denote methyl, ethyl, propyl, isopropyl, CF₃,C₂F₅, CH₂OCH₃, CH₂OC₂H₅, CH₂OCH(CH₃)₂, C₂H₅OCH₃; X denotes2-oxopyrrolidinyl, 2-oxopiperidyl, or 2-oxoazepanyl, each independentlyfrom each other unsubstituted or mono or disubstituted by A1 and/or Ar1;A1 denotes C1-C3-alkyl; Ar1 denotes phenyl, o-, m- or p-tolyl, o-, m- orp-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl,o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- orp-nitrophenyl, o-, m- or p-aminophenyl, o-, m- orp-(N-methylamino)phenyl, o-, m- or p-methoxyphenyl, o-, m- orp-ethoxyphenyl, o-, m- or p-(N,N-dimethylamino)phenyl, o-, m- orp-(N-ethylamino)phenyl, o-, m- or p-(N,N-diethylamino)phenyl, o-, m- orp-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-,m- or p-cyanophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethylphenyl,2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-,2,6-, 3,4- or 3,5-dichlorophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or3,4-dimethoxyphenyl; Cyc denotes phenyl, which is unsubstituted, mono-,disubstituted or trisubstituted by Hal, CN, R^(3a) or OR^(3a), whereindisubstitution is in 2,4-, or 3,4-position and trisubstitution is in2,3,4-position; or 1- or 2-naphthyl, each, independently from oneanother, unsubstituted, mono- or disubstituted by Hal, CN, R^(3a) orOR^(3a); and tautomers, stereoisomers or physiologically acceptablesalts thereof, including mixtures thereof in all ratios.
 5. The compoundaccording to claim 4, wherein Cyc denotes: 2,4-, 3,4-, or2,3,4-substituted phenyl or unsubstituted or mono- or disubstituted 1-or 2-naphthyl, wherein the substituents are each, independently from oneanother, selected from the group consisting of Hal, CN, R^(3a) orOR^(3a); or Cyc is a residue according to formula (Fa7) or (Fb7)

wherein: G^(a) denotes, F, Cl, Br, CN, R^(3a) or OR^(3a); G^(b) denotesH, F, Cl, Br, CN, R^(3a) or OR^(3a); K^(a) and K^(b) denote each,independently from one another, H, F, Cl, Br, CN, R^(3a) or OR^(3a);R^(3a) and R^(3b) denote each, independently from one another, linear orbranched C1-C3-alkyl, wherein 1 to 5H atoms may be replaced by F, Cl, OHand OAlk, wherein Alk is methyl or ethyl; and tautomers, stereoisomersor physiologically acceptable salts thereof, including mixtures thereofin all ratios.
 6. The compound according to claim 5, wherein Cycdenotes: 2,4-, 3,4-, or 2,3,4-substituted phenyl or unsubstituted ormono- or disubstituted 1- or 2-naphthyl, wherein the substituents areeach, independently from one another, selected from the group consistingof Hal, CN, R^(3a) OR^(3a); or Cyc is a residue according to formula(Fa7) or (S)-(Fb7)

wherein: G^(a) denotes F, Cl, Br, CN, R^(3a) or OR^(3a); G^(b) denotesH, F, Cl, Br, CN, R^(3a) or OR^(3a); K^(a) and K^(b) denote each,independently from one another, H, F, Cl, Br, CN, R^(3a) or OR^(3a);R^(3a) and R^(3b) denote each, independently from one another, linear orbranched C1-C3-alkyl, wherein 1 to 5H atoms may be replaced by F, Cl, OHand OAlk, wherein Alk is methyl or ethyl; and tautomers, stereoisomersor physiologically acceptable salts thereof, including mixtures thereofin all ratios.
 7. The compound according to claim 6, wherein Cycdenotes: 2,4-, 3,4-, or 2,3,4-substituted phenyl or unsubstituted ormono- or disubstituted 1- or 2-naphthyl, wherein the substituents areeach, independently from one another, selected from the group consistingof F, Cl, CH₃, C₂H₅, CF₃, OCH₃, OC₂H₅ or CH₂OCH₃; or Cyc is a residueaccording to formula (Fa7), (Fb7) or (S)-(Fb7), wherein: G^(a) denotesF, Cl, CH₃, C₂H₅, CF₃, OCH₃, OC₂H₅, COCF₃ or CH₂OCH₃; G^(b) denotes H,F, Cl, CH₃, C₂H₅, CF₃, OCH₃, OC₂H₅, COCF₃ or CH₂OCH₃; K^(a) and K^(b)denote each, independently from one another, H, F, Cl, CH₃, C₂H₅, CF₃,OCH₃, OC₂H₅, COCF₃ or CH₂OCH₃; and tautomers, stereoisomers orphysiologically acceptable salts thereof, including mixtures thereof inall ratios.
 8. The compound according to claim 1, wherein: LX denotes—CH₂—CH₂— or —CH₂—CH₂—CH₂—; and LY denotes —CH₂—; and Y denotes Cyc; andR¹, R² denote each, independently from one another H or C1-C4-alkyl, orR¹ and R² form together a residue according to formula (CE) as describedabove; and Ar1 denotes phenyl, o-, m- or p-tolyl, o-, m- orp-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl,o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- orp-nitrophenyl, o-, m- or p-aminophenyl, o-, m- orp-(N-methylamino)phenyl, o-, m- or p-methoxyphenyl, o-, m- orp-ethoxyphenyl, o-, m- or p-(N,N-dimethylamino)phenyl, o-, m- orp-(N-ethylamino)phenyl, o-, m- or p-(N,N-diethylamino)phenyl, o-, m- orp-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-,m- or p-cyanophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethylphenyl,2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-,2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl,3-amino-4-chloro-2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro-or 2-amino-6-chlorophenyl, 2-nitro-4-N,N-dimethylamino- or3-nitro-4-N,N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-,2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl,2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl,4-fluoro-3-chloro-phenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl,3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl,3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl; and Cycdenotes 2,4-, 3,4-, or 2,3,4-substituted phenyl or unsubstituted ormono- or disubstituted 1- or 2-naphthyl, wherein the substituents areeach, independently from one another, selected from the group consistingof Hal, CN, R^(3a) and OR^(3a) or a residue according to formula (Fa7)or (S)-(Fb7)

G^(a) denotes F, Cl, CH₃, C₂H₅, CF₃, OCH₃, OC₂H₅ or CH₂OCH₃; G^(b)denotes H, F, Cl, CH₃, C₂H₅, CF₃, OCH₃, OC₂H₅ or CH₂OCH₃; K^(a) andK^(b) denote each, independently from one another, H, F, Cl, CH₃, C₂H₅,CF₃, OCH₃, OC₂H₅ or CH₂OCH₃; and tautomers, stereoisomers orphysiologically acceptable salts thereof, including mixtures thereof inall ratios.
 9. The compound according to claim 1, said compound beingselected from the group consisting of:[(1S)-1-[3-(2-oxopyrrolidin-1-yl)propanoylamino]-2-phenyl-ethyl]boronicacid;[(1S)-1-[3-(2-oxo-1-piperidyl)propanoylamino]-2-phenyl-ethyl]boronicacid;[(1R)-1-[3-(2-oxopyrrolidin-1-yl)propanoylamino]-2-(p-tolyl)ethyl]boronicacid; [(1R)-2-(2-naphthyl)-1-[3-(2-oxopyrrolidin-1-yl)propanoylamino]ethyl] boronic acid;[(1R)-2-(2-naphthyl)-1-[3-(2-oxo-1-piperidyl)propanoylamino]ethyl]boronicacid;[(1R)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-[3-(2-oxopyrrolidin-1-yl)propanoylamino]ethyl]-boronicacid;[(1R)-1-[3-(2-oxo-1-piperidyl)propanoylamino]-2-(p-tolyl)ethyl]boronicacid;[(1R)-2-(1-naphthyl)-1-[3-(2-oxopyrrolidin-1-yl)propanoylamino]ethyl]boronicacid; [(1R)-2-(1-naphthyl)-1-[3-(2-oxo-1-piperidyl)propanoylamino]ethyl]boronic acid;[(1R)-1-[3-(2-oxo-4-phenyl-pyrrolidin-1-yl)propanoylamino]-2-phenyl-ethyl]boronicacid;[(1R)-1-[3-(2-oxoazepan-1-yl)propanoylamino]-2-phenyl-ethyl]boronicacid;[(1R)-2-(3,4-dimethylphenyl)-1-[3-(2-oxopyrrolidin-1-yl)propanoylamino]-ethyl]boronicacid;[(1R)-1-[3-(3,3-dimethyl-2-oxo-pyrrolidin-1-yl)propanoylamino]-2-(p-tolyl)ethyl]-boronicacid;[(1R)-1-[3-(2,2-dimethyl-5-oxo-pyrrolidin-1-yl)propanoylamino]-2-(p-tolyl)ethyl]-boronicacid;[(1R)-2-(benzofuran-3-yl)-1-[3-(2-oxopyrrolidin-1-yl)propanoylamino]ethyl]-boronic acid;[(1R)-2-[4-(methoxymethyl)phenyl]-1-[3-(2-oxopyrrolidin-1-yl)propanoylamino]-ethyl]boronicacid;[(1R)-1-[[2-(2-oxopyrrolidin-1-yl)acetyl]amino]-2-(p-tolyl)ethyl]boronicacid;[(1R)-1-[3-(1,1-dioxothiazinan-2-yl)propanoylamino]-2-(p-tolyl)ethyl]boronicacid;[(1R)-2-(benzofuran-3-yl)-1-[3-(2-oxo-1-piperidyl)propanoylamino]ethyl]boronicacid;[(1R)-2-(3,4-dimethylphenyl)-1-[3-(2-oxo-1-piperidyl)propanoylamino]ethyl] boronic acid;[(1R)-2-(benzofuran-3-yl)-1-[3-(1,1-dioxothiazinan-2-yl)propanoylamino]ethyl]-boronicacid;[(1R)-2-(benzofuran-3-yl)-1-[3-(2,2-dimethyl-5-oxo-pyrrolidin-1-yl)propanoylamino]ethyl]-boronicacid;[(1R)-2-(2,4-dimethylphenyl)-1-[3-(2-oxo-1-piperidyl)propanoylamino]ethyl]boronic acid;[(1R)-2-(2,4-dimethylphenyl)-1-[3-(1,1-dioxothiazinan-2-yl)propanoylamino]ethyl]-boronic acid;[(1R)-1-[3-(2,2-dimethyl-5-oxo-pyrrolidin-1-yl)propanoylamino]-2-(7-methylbenzofuran-3-yl)ethyl]boronicacid; [(1R)-2-[(3S)-2,3-dihydrobenzofuran-3-yl]-1-[3-(2-oxopyrrolidin-1-yl)propanoylamino]ethyl]boronicacid;[(1R)-2-[(3S)-7-methyl-2,3-dihydrobenzofuran-3-yl]-1-[3-(2-oxo-1-piperidyl)propanoylamino]ethyl]boronicacid; and tautomers thereof or physiologically acceptable salts thereof,including mixtures thereof in all ratios.
 10. A pharmaceuticalcomposition comprising at least one compound according to claim 1 ortautomers, stereoisomers or physiologically acceptable salts thereof,including mixtures thereof in all ratios, as active ingredient, togetherwith a pharmaceutically acceptable carrier.
 11. The pharmaceuticalcomposition according to claim 10, said composition further comprising asecond active ingredient or tautomers, stereoisomers or physiologicallyacceptable salts thereof, including mixtures thereof in all ratios,wherein that second active ingredient is other than a compound offormula (I).
 12. A kit consisting of separate packs of: (a) an effectiveamount of a compound according to claim 1 and/or tautomers,stereoisomers or physiologically acceptable salts thereof, includingmixtures thereof in all ratios, and (b) an effective amount of a furthermedicament active ingredient.